uu.seUppsala University Publications
Change search
Refine search result
12 1 - 50 of 62
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the 'Create feeds' function.
  • 1.
    Antoni, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Borg, Beatrice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    5-Fluoro-[beta-C-11]-L-tryptophan is a functional analogue of 5-hydroxy-[beta-C-11]-L-tryptophan in vitro but not in vivo2013In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 56, no S1, S367-S367 p.Article in journal (Other academic)
  • 2.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Palanisamy, Senthilkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Imaging the in vivo fate of human T cells following transplantation in immunoincompetent mice - Implications for clinical cell therapy trials2013In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 29, no 1-4, 105-108 p.Article in journal (Refereed)
    Abstract [en]

    Many forms of adoptive T cell therapy are on the verge of being translated to the clinic. To gain further insight in their immunomodulating functions and to optimize future clinical trials it is essential to develop techniques to study their homing capacity. CD4+ T cells were labeled using [In-111]oxine, and the radioactive uptake was determined in vitro before intravenous injection in immunodeficient mice. In vivo biodistribution of [In-111] oxine-labeled cells or tracer alone was subsequently measured by mu SPECT/CT and organ distribution. CD4+ T cells incorporated [In-111]oxine with higher labeling yield using Ringer-Acetate compared to 0.9% NaCl. Cellular viability after labeling with [In-111]oxine was not compromised using less than 0.4 MBq/million cells. After intravenous infusion CD4+ T cells preferentially homed to the liver (p < 0.01) and spleen (p < 0.05). This study presents a protocol for labeling of T cells by [In-111]oxine with preserved viability and in vivo tracking by SPECT for up to 8 days, which can easily be translated to clinical cell therapy trials. 

  • 3.
    Blom, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Karimi, Farhad
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hall, Håkan
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Synthesis and in vitro evaluation of 18F-β-carboline alkaloids as PET ligands2008In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 51, no 6, 277-282 p.Article in journal (Refereed)
    Abstract [en]

    A one-step 18F-labelling strategy was used to prepare four 18F-labelled analogues of 7-methoxy-1-methyl-9H-β-carboline (harmine): 7-(2-[18F]fluoroethoxy)-1-methyl-9H-β-carboline (5), 7-(3-[18F]fluoro-propoxy)-1-methyl-9H-β-carboline (6), 7-[2-(2-[18F]fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline (7), and 7-{2-[2-(2-[18F]fluoroethoxy)ethoxy]-ethoxy}-1-methyl-9H-β-carboline (8). These were synthesized as potential PET ligands for monoamine oxidase A. A solution of pure labelled compound in buffer was obtained in < 70 min from end of radionuclide production, with a decay-corrected yield of up to 23%. The average specific binding to MAO-A in rat brain, determined by autoradiography experiments, was highest for compounds 7 and 8 (89 ± 2 and 96 ± 1% respectively), which was obtained at < 1 nM radioligand concentration.

  • 4. Blomberg, Bjoern A.
    et al.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Saboury, Babak
    Alavi, Abass
    beta-Cell Mass Imaging with DTBZ Positron Emission Tomography: Is it Possible?2013In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 15, no 1, 1-2 p.Article in journal (Refereed)
  • 5.
    Bulenga, T. N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Dosimetry of 68Ga and 177Lu labeled Exendin4-impact on feasibility of repeated PET imaging and radiotherapy2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, S293-S293 p., OP607Article in journal (Other academic)
  • 6.
    Carlbom, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 9, 1968-1972 p.Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The aim of this study was to investigate pancreatic perfusion and its response to a glucose load in patients with type 1 diabetes mellitus compared with non-diabetic ('healthy') individuals.

    METHODS: Eight individuals with longstanding type 1 diabetes and ten sex-, age- and BMI-matched healthy controls underwent dynamic positron emission tomography scanning with (15)O-labelled water before and after intravenous administration of glucose. Perfusion in the pancreas was measured. Portal and arterial hepatic perfusion were recorded as references.

    RESULTS: Under fasting conditions, total pancreatic perfusion was on average 23% lower in the individuals with diabetes compared with healthy individuals. Glucose increased total pancreatic and portal hepatic blood perfusion in healthy individuals by 48% and 38%, respectively. In individuals with diabetes there was no significant increase in either total pancreatic or portal hepatic perfusion.

    CONCLUSIONS/INTERPRETATION: Individuals with type 1 diabetes have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation.

  • 7.
    Carlbom, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    [(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes2017In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 5, 1286-1292 p.Article in journal (Refereed)
    Abstract [en]

    [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP) PET of the pancreas has been shown to be a surrogate imaging biomarker of pancreatic islet mass. The change in islet mass in different stages of type 2 diabetes (T2D) as measured by non-invasive imaging is currently unknown. Here, we describe a cross-sectional study where subjects at different stages of T2D development with expected stratification of pancreatic islet mass were examined in relation to non-diabetic individuals. The primary outcome was the [(11)C]5-HTP uptake and retention in pancreas, as a surrogate marker for the endogenous islet mass.We found that metabolic testing indicated a progressive loss of beta cell function, but that this was not mirrored by a decrease in [(11)C]5-HTP tracer accumulation in the pancreas. This provides evidence of retained islet mass despite decreased beta cell function. The results herein indicates that beta cell dedifferentiation, and not necessarily endocrine cell loss, constitute a major cause of beta cell failure in T2D.

  • 8.
    Eich, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundgren, Torbjörn
    Visualization of early engraftment in clinical islet transplantation by positron-emission tomography2007In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 356, no 26, 2754-2755 p.Article in journal (Refereed)
  • 9.
    Eich, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Estrada, Sergio
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundgren, Torbjörn
    Positron emission tomography: A real-time tool to quantify early islet engraftment in a preclinical large animal model2007In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, no 7, 893-898 p.Article in journal (Refereed)
    Abstract [en]

    Background. Clinical islet transplantation is currently being explored as a therapeutic option for persons with type I diabetes and hypoglycemic unawareness. Techniques to monitor graft survival are urgently needed to optimize the procedure. Therefore, the objective of the present study was to develop a technique for imaging survival of transplanted islets in the peritransplant and early posttransplant phase.

    Methods. Isolated porcine islets were labeled in vitro with 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) and infused intraportally into anesthetized pigs (n=10). Dynamic examination was performed on a positron emission tomography/computed tomography hybrid system.

    Results. More than 95% of the radioactivity was confined to the islets at the time of transplantation. The peak percentage of infused radioactivity within the liver, quantified at the end of the islet infusion, was only 54±5.1%. The distribution of the radioactivity in the liver was found to be heterogeneous. A whole-body examination showed no accumulation in the lungs or brain; extrahepatic radioactivity was, except urinary excretion, evenly distributed in the pig body.

    Conclusions. Our results imply that almost 50% of the islets were damaged to the extent that the FDG contained was release within minutes after intraportal transplantation. The distribution of radioactivity without accumulation in the brain indicates that the activity is released from lysed islet cells in the form of [18F]FDG-6P rather than native [18F]FDG. The presented technique shows promise to become a powerful and quantitative tool, readily available in the clinic, to evaluate initial islet engraftment and survival.

  • 10.
    Eriksson, J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    5-Hydroxy-L-[beta-C-11]-tryptophan Deuterium Isotopologue Shows Increased Retention In Neuro-endocrine Cells Due To Secondary Kinetic Isotope Effect2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, S261-S261 p., OP466Article in journal (Other academic)
  • 11.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Strategy to develop a MAO-A-resistant 5-hydroxy-L-[beta-C-11]tryptophan isotopologue based on deuterium kinetic isotope effects2014In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 4, no 1, 62Article in journal (Refereed)
    Abstract [en]

    Background

    The serotonin precursor 5-hydroxy-L-[β-11C]tryptophan ([11C]HTP) is in clinical use for localization of neuroendocrine tumors and has been suggested as a proxy marker for pancreatic islet cells. However, degradation by monoamine oxidase-A (MAO-A) reduces retention and the contrast to non-endocrine tissue.

    Methods

    A synthesis method was developed for 5-hydroxy-L-[β-11C2H]tryptophan ([11C]DHTP), an isotopologue of [11C]HTP, labeled with 11C and 2H at the β-position adjacent to the carbon involved in MAO-A decarboxylation. MAO-A-mediated degradation of [11C]DHTP was evaluated and compared to non-deuterated [11C]HTP.

    Results

    [11C]DHTP was synthesized with a radiochemical purity of >98%, radioactivity of 620 ± 190 MBq, and deuterium (2H or 2H2) incorporation at the β-position of 22% ±5%. Retention and resistance to MAO-A-mediated degradation of [11C]DHTP were increased in cells but not in non-human primate pancreas.

    Conclusions

    Partial deuteration of the β-position yields improved resistance to MAO-A-mediated degradation in vitro but not in vivo.

  • 12.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Imaging Islets of Langerhans by Positron Emission Tomography: Quantification of Beta-Cell Mass in the Native Pancreas and the Islet Graft2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 1 and 2 Diabetes Mellitus are a growing health problem throughout the world. There is an increasing  need for methodologies, which are both reliable and non-invasive to measure the amount of insulin-producing tissue (Beta-cell mass, or BCM), as well as rapidly quantify changes in the BCM due to the onset of disease, beta-cell replacement therapy, or other treatments.

    Positron Emission Tomography (PET) is a non-invasive, quantitative functional imaging technique which can be used to study dynamical or static processes inside the body.

    In this thesis, we present a study protocol for in vivo imaging of the most common form of beta- cell replacement therapy; islet transplantation. Islets were labeled with the PET tracer, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG), and administered intra-portally, while the recipient was monitored by PET/CT. The hepatic distribution of the islets was highly heterogeneous, and around 25% (human) or 50% (porcine) of the administered islets could not be found in the liver after completed transplantation, confirming previous reports of considerable cell injury during the procedure leading to low hepatic engraftment.

    Native BCM in the pancreas can potentially be quantified using a PET tracer with sufficiently high specificity, but the major obstacle is the relative low amounts of insulin producing tissue (only 1-2% of the pancreatic volume). Two tetrabenazine analogues, [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, are ligands to VMAT2, which is expressed in islet tissue. Both analogues were investigated and characterized as potential BCM imaging agents both in vitro and in vivo.  Both tracers exhibited high preferential binding to islet tissue compared to exocrine pancreatic tissue. However, the specificity was not high enough to overcome the obscuring exocrine signal in vivo (7-10% of the signal originating from specific islet tracer uptake).

    This thesis demonstrates that it is possible to quantitatively assess islet transplantation by PET imaging. In vivo determination of native pancreatic BCM is, in theory, possible with both [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, but tracer analogues with higher islet specificity is needed for quantification of smaller BCM changes with physiological impact.

    List of papers
    1. Positron emission tomography: A real-time tool to quantify early islet engraftment in a preclinical large animal model
    Open this publication in new window or tab >>Positron emission tomography: A real-time tool to quantify early islet engraftment in a preclinical large animal model
    Show others...
    2007 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, no 7, 893-898 p.Article in journal (Refereed) Published
    Abstract [en]

    Background. Clinical islet transplantation is currently being explored as a therapeutic option for persons with type I diabetes and hypoglycemic unawareness. Techniques to monitor graft survival are urgently needed to optimize the procedure. Therefore, the objective of the present study was to develop a technique for imaging survival of transplanted islets in the peritransplant and early posttransplant phase.

    Methods. Isolated porcine islets were labeled in vitro with 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) and infused intraportally into anesthetized pigs (n=10). Dynamic examination was performed on a positron emission tomography/computed tomography hybrid system.

    Results. More than 95% of the radioactivity was confined to the islets at the time of transplantation. The peak percentage of infused radioactivity within the liver, quantified at the end of the islet infusion, was only 54±5.1%. The distribution of the radioactivity in the liver was found to be heterogeneous. A whole-body examination showed no accumulation in the lungs or brain; extrahepatic radioactivity was, except urinary excretion, evenly distributed in the pig body.

    Conclusions. Our results imply that almost 50% of the islets were damaged to the extent that the FDG contained was release within minutes after intraportal transplantation. The distribution of radioactivity without accumulation in the brain indicates that the activity is released from lysed islet cells in the form of [18F]FDG-6P rather than native [18F]FDG. The presented technique shows promise to become a powerful and quantitative tool, readily available in the clinic, to evaluate initial islet engraftment and survival.

    Keyword
    Imaging, Islets, PET scanning, Transplantation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-14994 (URN)10.1097/01.tp.0000284730.86567.9f (DOI)000250232600014 ()17984843 (PubMedID)
    Available from: 2008-06-05 Created: 2008-06-05 Last updated: 2017-12-11Bibliographically approved
    2. Visualization of early engraftment in clinical islet transplantation by positron-emission tomography
    Open this publication in new window or tab >>Visualization of early engraftment in clinical islet transplantation by positron-emission tomography
    2007 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 356, no 26, 2754-2755 p.Article in journal, Letter (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-103621 (URN)000247564500035 ()17596618 (PubMedID)
    Available from: 2009-05-20 Created: 2009-05-20 Last updated: 2017-12-13Bibliographically approved
    3. Positron emission tomography in clinical islet transplantation
    Open this publication in new window or tab >>Positron emission tomography in clinical islet transplantation
    Show others...
    2009 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 9, no 12, 2816-2824 p.Article in journal (Refereed) Published
    Abstract [en]

    The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants. A fraction of the islets (23%) were labeled with 18F-fluorodeoxyglucose ([(18)F]FDG) and carefully mixed with unlabeled islets just prior to intraportal transplantation. The peak radioactivity concentration in the liver was found at 19 min after start of islet infusion and corresponded to only 75% of what was expected, indicating that islets are lost during the transplantation procedure. No accumulation of radioactivity was found in the lungs. A nonphysiological peak of C-peptide was found in plasma during and immediately after transplantation in all subjects. Distribution in the liver was heterogeneous with wide variations in location and concentration. Islets found in areas with concentrations of >400 IEQ/cc liver tissue varied between 1% and 32% of the graft in different subjects. No side effects attributed to the PET/CT procedure were found. Clinical outcome in all patients was comparable to that previously observed indicating that the [(18)F]FDG labeling procedure did not harm the islets. The technique has potential to be used to assess approaches to enhance islet survival and engraftment in clinical transplantation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-111860 (URN)10.1111/j.1600-6143.2009.02844.x (DOI)000272127600023 ()19845588 (PubMedID)
    Available from: 2009-12-28 Created: 2009-12-28 Last updated: 2017-12-12Bibliographically approved
    4. In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass
    Open this publication in new window or tab >>In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass
    Show others...
    2010 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, no 3, 357-363 p.Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: The positron emission tomography (PET) tracer 9-[(18)F]fluoroethyl-(+)-dihydrotetrabenazine ([(18)F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass.

    METHODS: Three pigs were intravenously administered [(18)F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k(D) and B(max) were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls.

    RESULTS: [(18)F]-FE-(+)-DTBZ had a k(D) of 3.5+/-1.0 nM, a B(max) of 382+/-108 fmol/mg protein and a specificity of 89+/-1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone.

    CONCLUSIONS: [(18)F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [(18)F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.

    Keyword
    Positron emission tomography, DTBZ, Beta-cell mass, VMAT2
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-136369 (URN)10.1016/j.nucmedbio.2009.12.004 (DOI)000276551800013 ()20346875 (PubMedID)
    Available from: 2010-12-12 Created: 2010-12-12 Last updated: 2017-12-11Bibliographically approved
    5. Decreased defluorination by using the novel beta cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET
    Open this publication in new window or tab >>Decreased defluorination by using the novel beta cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Fluorine-18 DTBZ-analogues, which selectively targets the vesicular monoamine transporter 2 (VMAT2), have been extensively studied for in vivo quantification of beta cell mass by positron emission tomography (PET).  This study describes a novel deuterated radioligand [18F]FE-(+)-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [18F]FE-(+)-DTBZ.

    Methods: [18F]FE-(+)-DTBZ-d4 was synthesized by alkylation of desmethyl -(+)-DTBZ precursor with deuterated  [18F]fluoroethyl bromide ([18F]FCD2CD2Br). Radioligand affinity and specificity to VMAT2 was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo PK/PD was studied in a porcine model by PET/CT. The rate of defluorination was quantified by compartmental modeling and contrasted against defluorination of the non-deuterated analogue.

    Results: [18F]FE-DTBZ-d4 was produced in good radiochemical yield (3.0-1.7 GBq) in 100 min. Radiochemical purity of the formulated product was > 98% for up to 5h. The in vitro Binding Potential (BP) for VMAT2 in islet tissue was 27.0±8.8. The BP was lower in exocrine tissue (1.7±1.0) in addition to a close to three-fold decrease in specificity. The rate of in vivo defluorination was decreased significantly (kdefluorination= 0.0016±0.0007) compared to the non-deuterated analogue (kdefluorination= 0.012±0.002), resulting in a more than six-fold increase in half-life stability.

    Conclusion: [18F]FE-(+)-DTBZ-d4 has favorable pharmacokinetic (PK) properties for VMAT2 imaging, in addition to gaining significantly increased stability against defluorination. The in vitro islet BP and specificity was lower compared to a non-deuterated analogue but the islet/exocrine BP ratio was unchanged, potentially allowing for improved target tissue discrimination.

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-136370 (URN)
    Available from: 2010-12-12 Created: 2010-12-12 Last updated: 2018-01-12
  • 13.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Alavi, Abass
    Imaging the islet graft by positron emission tomography2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no 3, 533-542 p.Article, review/survey (Refereed)
    Abstract [en]

    Clinical islet transplantation is being investigated as a permanent cure for type 1 diabetes mellitus (T1DM). Currently, intraportal infusion of islets is the favoured procedure, but several novel implantation sites have been suggested. Noninvasive longitudinal methodologies are an increasingly important tool for assessing the fate of transplanted islets, their mass, function and early signs of rejection. This article reviews the approaches available for islet graft imaging by positron emission tomography and progress in the field, as well as future challenges and opportunities.

  • 14.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    [C-11] Carfentanil Binds Preferentially to mu-Opioid Receptor Subtype 1 Compared to Subtype 22015In: Molecular Imaging, ISSN 1535-3508, E-ISSN 1536-0121, Vol. 14, 476-483 p.Article in journal (Refereed)
    Abstract [en]

    The positron emission tomography (PET) ligand [C-11] carfentanil is a selective agonist for mu-opioid receptors and has been used for studying mu-opioid receptors in the human brain. However, it is unknown if [C-11] carfentanil binding differentiates between subtype receptors mu(1) and mu(2). In this study, we investigated whether mu(1) and mu(2) can be studied separately through receptor subtype-selective inhibition of [C-11] carfentanil by pharmacologic intervention. [C-11] Carfentanil binding characteristics on rat brain sections were assessed either alone or in the presence of the mu-receptor inhibitor cyprodime or the mu(1)-specific inhibitor naloxonazine. [C-11] Carfentanil binding in the living rat brain was similarly studied by small animal PET/computed tomography during baseline conditions or following displacement by cyprodime or naloxonazine. Autoradiography binding studies on rat brain sections demonstrated that [C-11] carfentanil has higher affinity and binding potential for mu(1) than for mu(2). [C-11] Carfentanil binding to mu(2) in vivo could not be detected following specific blocking of mu(1), as predicted from the low binding potential for mu(2) as measured in vitro. [C-11] Carfentanil binding is preferential for mu(1) compared to mu(2) in vitro and in vivo. Clinical studies employing [C-11] carfentanil are therefore likely biased to measure mu(1) rather than mu(2).

  • 15.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Carlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Blom, Elisabeth
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Preclinical evaluation of a 68Ga-labeled biotin analogue for applications in islet transplantation2012In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 3, 415-421 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Islet transplantation is a promising treatment for type 1 diabetes mellitus, but the fate of the cells after intraportal infusion is unclear. It is therefore imperative to develop novel techniques for noninvasive imaging and quantification of events following islet transplantation.

    METHODS:

    Small islet-like microbeads, avidin-covered agarose resins (AARs), were used as a model system for islet transplantation. Capability for specific [(68)Ga]Ga-DOTA-(PEG)(2)-biotin uptake and retention for either AARs or human islets conjugated with avidin by means of a heparin scaffold was studied in vitro. Biodistribution of the novel positron emission tomography (PET) tracer [(68)Ga]Ga-DOTA-(PEG)(2)-biotin was evaluated in mice treated by intraportal transplantation of AARs by μPET/computed tomography and ex vivo organ distribution and compared with control mice.

    RESULTS:

    AARs had high capability to bind [(68)Ga]Ga-DOTA-(PEG)(2)-biotin, close to 50% of administrated tracer/μl in vitro (>0.25 MBq/μl). Avidin-tagged human islets could bind on average 2.2% of administered tracer/μl. Specificity (>90%) and retention (>90% after 1 h) were high for both AARs and avidin-tagged islets. Hepatic tracer uptake and retention were increased in mice transplanted with AARs [standardized uptake value (SUV)=2.6] compared to the untreated group (SUV=1.4). In vivo uptake of tracer to AARs was blocked by preadministration of unlabeled biotin.

    CONCLUSIONS:

    Avidin-tagged islet-like objects can be tracked in hepatic volume after intraportal transplantation by using [(68)Ga]Ga-DOTA-(PEG)(2)-biotin and PET.

  • 16.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Eich, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Andersson, H.
    Felldin, M.
    Foss, A.
    Kyllönen, L.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Lundgren, Torbjörn
    Positron emission tomography in clinical islet transplantation2009In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 9, no 12, 2816-2824 p.Article in journal (Refereed)
    Abstract [en]

    The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants. A fraction of the islets (23%) were labeled with 18F-fluorodeoxyglucose ([(18)F]FDG) and carefully mixed with unlabeled islets just prior to intraportal transplantation. The peak radioactivity concentration in the liver was found at 19 min after start of islet infusion and corresponded to only 75% of what was expected, indicating that islets are lost during the transplantation procedure. No accumulation of radioactivity was found in the lungs. A nonphysiological peak of C-peptide was found in plasma during and immediately after transplantation in all subjects. Distribution in the liver was heterogeneous with wide variations in location and concentration. Islets found in areas with concentrations of >400 IEQ/cc liver tissue varied between 1% and 32% of the graft in different subjects. No side effects attributed to the PET/CT procedure were found. Clinical outcome in all patients was comparable to that previously observed indicating that the [(18)F]FDG labeling procedure did not harm the islets. The technique has potential to be used to assess approaches to enhance islet survival and engraftment in clinical transplantation.

  • 17.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Jansson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 10, 3428-3437 p.Article in journal (Refereed)
    Abstract [en]

    In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.

  • 18.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Jahan, Mahabuba
    Johnström, Peter
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Halldin, Christer
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass2010In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, no 3, 357-363 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The positron emission tomography (PET) tracer 9-[(18)F]fluoroethyl-(+)-dihydrotetrabenazine ([(18)F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass.

    METHODS: Three pigs were intravenously administered [(18)F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k(D) and B(max) were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls.

    RESULTS: [(18)F]-FE-(+)-DTBZ had a k(D) of 3.5+/-1.0 nM, a B(max) of 382+/-108 fmol/mg protein and a specificity of 89+/-1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone.

    CONCLUSIONS: [(18)F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [(18)F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.

  • 19.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Josephsson, Ray
    Långström, Bengt
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Positron emission tomography and target-controlled infusion for precise modulation of brain drug concentration2008In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 35, no 3, 299-303 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: There are several instances when it is desirable to control brain concentration of pharmaceuticals, e.g., to modulate the concentration of anesthetic agents to different desired levels fitting to different needs during the course of surgery. This has so far only been possible using indirect estimates of drug concentration such as assuming constant relation between tissue and blood including extrapolations from animals. Methods: A system for controlling target tissue concentration (UIPump) was used to regulate whole-brain concentrations of a central benzodiazepine receptor antagonist at therapeutic levels with input from brain kinetics as determined with PET. The system was tested by using pharmacological doses of flumazenil mixed with tracer amounts of [C-11]flumazenil. Flumazenil was used as a model compound for anesthesia. An infusion scheme to produce three different steady-state levels in sequence was designed based on kinetic curves obtained after bolus injection. The subjects (Sprague-Dawley rats, n = 6) were monitored in a microPET scanner during the whole experiment to verify resulting brain kinetic curves. Results: A steady-state brain concentration was rapidly achieved corresponding to a whole-brain concentration of 118 +/- 6 ng/ml. As the infusion rate decreased to lower the exposure by a factor of 2, the brain concentration decreased to 56 +/- 4 ng/ml. A third increased steady-state level of anesthesia corresponding to a whole-brain concentration of 107 +/- 7 ng/ml was rapidly achieved. Conclusion: The experimental setup with computerized pump infusion and PET supervision enables accurate setting of target tissue drug concentration.

  • 20.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Langström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Josephsson, Ray
    Assessment of receptor occupancy-over-time of two dopamine transporter inhibitors by [C-11]CIT and target controlled infusion2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 2, 100-106 p.Article in journal (Refereed)
    Abstract [en]

    Introduction. Occupancy-over-time was determined for two dopamine transporter (DAT) inhibitors through modeling of their ability to displace the PET ligand [C-11]CIT. The tracer was held at a pseudo steady state in a reference tissue by target controlled infusion. Methods. Rhesus monkeys (n = 5) were given [C-11]CIT and studied with a PET scanner. Tracer uptake in the reference tissue cerebellum was held at a pseudo steady state by use of target controlled infusion. The pharmacokinetics/pharmacodynamics (PK/PD) of [C-11]CIT was assessed through the simplified reference tissue model (SRTM). Bupropion (n = 2) and GBR-12909 (n = 2) receptor occupancies were estimated through modeling of their effects on [C-11]CIT displacement. Results. There was a high uptake of [C-11]CIT in striatum, which contains a high DAT density. The reference tissue cerebellum had a comparatively low uptake. The modeling of [C-11]CIT PK/PD properties in striatum showed high binding potential (BP = 5.34 +/- 0.78). Both DAT inhibitors caused immediate displacement of [C-11]CIT after administration. The occupancy-over-time was modeled as a mono-exponential function, describing initial maximal occupancy (Occ(0)) and rate of ligand-receptor dissociation (k(off)). GBR-12909 showed irreversible binding (k(off) = 0) after an initial occupancy of 76.1%. Bupropion had a higher initial occupancy (84.5%) followed by a release half-life of 33 minutes (k(off) = 0.021). Conclusions. The proposed model can be used for assessment of in-vivo occupancy-over-time of DAT ligands by use of target controlled infusion of [C-11]CIT. The concept of assessing drug-receptor interactions by studying perturbations of a PET tracer from a pseudo steady state can be transferred to other CNS systems.

  • 21.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Univ Turku, Turku PET Ctr, Turku, Finland.;Abo Akad Univ, Dept Biosci, Turku, Finland..
    Laughlin, Maren
    NIDDK, NIH, Bethesda, MD 20892 USA..
    Brom, Maarten
    Radboud Univ Nijmegen, Dept Radiol & Nucl Med, Med Ctr, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    Nuutila, Pirjo
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Roden, Michael
    Univ Dusseldorf, Fac Med, Dept Endocrinol & Diabetol, Dusseldorf, Germany.;Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany..
    Hwa, Albert
    JDRF, Discovery Res, New York, NY USA..
    Bonadonna, Riccardo
    Univ Parma, Dept Clin & Expt Med, Div Endocrinol, I-43100 Parma, Italy.;AOU Parma, Parma, Italy..
    Gotthardt, Martin
    Radboud Univ Nijmegen, Dept Radiol & Nucl Med, Med Ctr, POB 9101, NL-6500 HB Nijmegen, Netherlands..
    In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 7, 1340-1349 p.Article, review/survey (Refereed)
    Abstract [en]

    Radiotracer imaging is characterised by high in vivo sensitivity, with a detection limit in the lower picomolar range. Therefore, radiotracers represent a valuable tool for imaging pancreatic beta cells. High demands are made of radiotracers for in vivo imaging of beta cells. Beta cells represent only a small fraction of the volume of the pancreas (usually 1-3%) and are scattered in the tiny islets of Langerhans throughout the organ. In order to be able to measure a beta cell-specific signal, one has to rely on highly specific tracer molecules because current in vivo imaging technologies do not allow the resolution of single islets in humans non-invasively. Currently, a considerable amount of preclinical data are available for several radiotracers and three are under clinical evaluation. We summarise the current status of the evaluation of these tracer molecules and put forward recommendations for their further evaluation.

  • 22.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Mintz, Akiva
    Liu, Chengyang
    Yu, Ming
    Naji, Ali
    Alavi, Abass
    On the use of [F-18]DOPA as an imaging biomarker for transplanted islet mass2014In: Annals of Nuclear Medicine, ISSN 0914-7187, E-ISSN 1864-6433, Vol. 28, no 1, 47-52 p.Article in journal (Refereed)
    Abstract [en]

    Aim

    Islet transplantation is being developed as a potential cure for patients with type 1 diabetes. There is a need for non-invasive imaging techniques for the quantification of transplanted islets, as current transplantation sites are associated with a substantial loss of islet viability. The dopaminergic metabolic pathway is present in the islets; therefore, we propose Fluorine-18 labeled l-3,4-dihydroxyphenylalanine ([F-18]DOPA) as a biomarker for transplanted islet mass.

    Methods

    The expression of enzymes involved in the dopaminergic metabolic pathway was investigated in both native and transplanted human islets. The specific uptake of [F-18]DOPA in islets and immortalized beta cells was studied in vitro by selective blocking of dopa decarboxylase (DDC). Initial in vivo PET imaging of viable subcutaneous human islets was performed using [F-18]DOPA.

    Results

    DDC and vesicular monoamine transporter 2 are co-localized with insulin in the native human pancreas, and the expression is retained after transplantation. Islet uptake of the [F-18]DOPA could be modulated by inhibiting DDC, indicating that the uptake followed the normal dopaminergic metabolic pathway. In vivo imaging revealed [F-18]DOPA uptake at the site of the functional islet graft. Based on the in vitro and in vivo results presented in this study, we propose to further validate [F-18]DOPA-PET as a sensitive imaging modality for imaging extrahepatically transplanted islets.

  • 23.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sadeghi, Arian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eich, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lundgren, Torbjörn
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tötterman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Distribution of adoptively transferred porcine T-lymphoblasts tracked by (18)F-2-fluoro-2-deoxy-D-glucose and position emission tomography2011In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 38, no 6, 827-833 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Autologous or allogeneic transfer of tumor-infiltrating T-Iymphocytes is a promising treatment for metastatic cancers, but a major concern is the difficulty in evaluating cell trafficking and distribution in adoptive cell therapy. This study presents a method of tracking transfusion of T-Iymphoblasts in a porcine model by (18)F-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) and positron emission tomography. Methods: T-Iymphoblasts were labeled with the positron-emitting tracer [(18)F]FDG through incubation. The T-Iymphoblasts were administered into the bloodstream, and the distribution was followed by positron emission tomography for 120 min. The cells were administered either intravenously into the internal jugular vein (n=5) or intraarterially into the ascending aorta (n=1). Two of the pigs given intravenous administration were pretreated with low-molecular-weight dextran sulphate. Results: The cellular kinetics and distribution were readily quantifiable for up to 120 min. High (78.6% of the administered cells) heterogeneous pulmonary uptake was found after completed intravenous transfusion. The pulmonary uptake was decreased either by preineubating and coadministrating the T-Iymphoblasts with low-molecular-weight dextran sulphate or by administrating them intraarterially. Conclusions: The present work shows the feasibility of quantitatively monitoring and evaluating cell trafficking and distribution following administration of [(18)F]FDG-labeled T-Iymphoblasts. The protocol can potentially be transferred to the clinical setting with few modifications.

  • 24.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Quantitative Imaging of Serotonergic Biosynthesis and Degradation in the Endocrine Pancreas2014In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 3, 460-465 p.Article in journal (Refereed)
    Abstract [en]

    Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the major constituent, has been implicated in insulin release and β cell proliferation. In this study, we investigated the feasibility of quantitative noninvasive imaging of the serotonergic metabolism in the pancreas using the PET tracer (11)C-5-hydroxy-l-tryptophan ((11)C-5-HTP).

    METHODS: Uptake of (11)C-5-HTP, and its specificity for key enzymes in the serotonergic metabolic pathway, was assessed in vitro (INS-1 and PANC1 cells and human islet and exocrine preparations) and in vivo (nonhuman primates and healthy and diabetic rats).

    RESULTS: In vitro tracer uptake in endocrine cells (INS-1 and human islets), but not PANC1 and exocrine cells, was mediated specifically by intracellular conversion into serotonin. Pancreatic uptake of (11)C-5-HTP in nonhuman primates was markedly decreased by inhibition of the enzyme dopa decarboxylase, which converts (11)C-5-HTP to (11)C-serotonin and increased after inhibition of monoamine oxidase-A, the main enzyme responsible for serotonin degradation. Uptake in the rat pancreas was similarly modulated by inhibition of monoamine oxidase-A and was reduced in animals with induced diabetes.

    CONCLUSION: The PET tracer (11)C-5-HTP can be used for quantitative imaging of the serotonergic system in the endocrine pancreas.

  • 25.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Borg, Beatrice
    Uppsala akademiska sjukhus, PET centrum.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    5-Fluoro-[beta-C-11]-L-tryptophan is a functional analogue of 5-hydroxy-[beta-C-11]-L-tryptophan in vitro but not in vivo2013In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 40, no 4, 567-575 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: 5-Hydroxy-[β-(11)C]-L-tryptophan ([(11)C]HTP) is an established positron emission tomography (PET) imaging agent for neuroendocrine tumors (NETs). It has also been used for other clinical research purposes in neurology and diabetes. However, its widespread use is limited by the short physical half-life of the radionuclide and a difficult radiosynthesis. Therefore, a Fluorine-18 labeled analogue, 5-[(18)F]Fluoro-L-tryptophan ([(18)F]FTRP), has been proposed as a functional analogue. There is no published method for the synthesis of L-[(18)F]FTRP. We have therefore developed a synthesis of 5-fluoro-[β-(11)C]-L-tryptophan ([(11)C]FTRP), based on the existing chemo-enzymatic method for [(11)C]HTP and evaluated the potential usefulness of radiolabeled FTRP as a substitute for [(11)C]HTP.

    METHODS: The in vitro and in vivo behavior of [(11)C]FTRP, including the dependence of key enzymes in the serotonergic metabolic pathway, was investigated in NET cell lines, NET xenograft carrying immunodeficient mice, normal rats and in non-human primate. [(11)C]HTP was used for direct comparison.

    RESULTS: Uptake of [(11)C]FTRP in NET cell lines in vitro was mediated by enzymes involved in serotonin synthesis and metabolism, similar to [(11)C]HTP. In vivo biodistribution, either in rodent or non-human primate, was not affected by selectively inhibiting enzymatic steps in the serotonergic metabolic pathway.

    CONCLUSION: [(11)C]FTRP has in vitro biological function similar to that of [(11)C]HTP. However, this function is not retained in vivo as shown by biodistribution and PET/CT studies. Radiolabeled FTRP is thus not likely to provide an advantage over [(11)C]HTP in PET imaging in oncology, neurology or diabetes.

  • 26.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sjöberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Functional Imaging of the Pancreatic Graft by Positron Emission Tomography2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, S94-S94 p.Article in journal (Other academic)
  • 27.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Kandeel, Fouad
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Detection of Metastatic Insulinoma by Positron Emission Tomography with [(68)Ga]Exendin-4 -: a case report2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 5, 1519-1524 p.Article in journal (Refereed)
    Abstract [en]

    Context:

    Insulinomas are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in non-diabetic adult patients. They are usually benign and curative surgery is the "gold standard" treatment if they can be localized. Malignant insulinomas are seen in less than 10% and their prognosis is poor. The Glucagon Like Peptide-1 receptor (GLP-1R) is markedly upregulated in insulinomas - especially benign lesions which are difficult to localize with current imaging techniques.

    Objective:

    To assess the possibility of the detection of primary and metastatic insulinoma by PET using [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 ([(68)Ga]Exendin-4) in a patient with severe hypoglycemia.

    Design:

    Dynamic and static PET/CT examination of a patient using [68Ga]Exendin-4.

    Setting:

    Uppsala University Hospital, Uppsala, Sweden.

    Patients:

    A patient presented with hypoglycemia requiring continuous intravenous glucose infusions. A pancreatic insulinoma was suspected and an exploratory laparotomy was urgently performed. At surgery, a tumor in the pancreatic tail with an adjacent metastasis was found and a distal pancreatic resection (plus splenectomy) and removal of lymph node was performed. Histopathology showed a WHO grade II insulinoma. Postoperatively hypoglycemia persisted but a PET/CT examination using the neuroendocrine marker [(11)C]-5-hydroxy-L-tryptophan was negative.

    Interventions:

    The patient was administered with [(68)Ga]Exendin-4 and examined by dynamic PET over the liver and pancreas.

    Main Outcome Measures:

    N/A

    Results:

    The stable GLP-1 analogue Exendin-4 was labeled with (68)Ga for PET imaging of GLP-1R expressing tumors. The patient was examined by [(68)Ga]Exendin-4-PET/CT which confirmed several small GLP-1R positive lesions in the liver and a lymph node that could not be conclusively identified by other imaging techniques. The results obtained from the [(68)Ga]Exendin-4-PET/CT examination provided the basis for continued systemic treatment.

    Conclusion:

    The results of the [(68)Ga]Exendin-4-PET/CT examination governed the treatment strategy of this particular patient and demonstrated the potential of this technique for future management of patients with this rare, but potentially fatal disease.

  • 28.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Wallberg, Andreas
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Josephsson, Raymond
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A computerized Infusion Pump for control of tissue tracer concentration during Positron Emission Tomography in vivo Pharmacokinetic/Pharmacodynamic measurements2008In: BMC Medical Physics, ISSN 1756-6649, E-ISSN 1756-6649, Vol. 8, no 2Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    A computer controlled infusion pump (UIPump) for regulation of target tissue concentration of radioactive compounds was developed for use in biological research and tracer development for PET.

    METHODS:

    Based on observed tissue or plasma kinetics after a bolus injection of the tracer an algorithm calculates the infusion needed to obtain a specified target kinetic curve. A computer feeds this infusion scheme into an infusion pump connected to an animal via a venous catheter. The concept was validated using [11C]Flumazenil administrated to Sprague-Dawley rats where the whole brain distribution and kinetic of the tracer was measured over time using a microPET-scanner. The accuracy and precision of the system was assessed by producing steady-state levels of the tracer and by mimicking kinetics after oral administration.

    RESULTS:

    Various kinetic profiles could be generated, including rapid achievement of constant levels, or step-wise increased levels. The resulting tissue curves had low deviation from the target curves according to the specified criteria: AUC (%): 4.2 +/- 2.8, Maximal deviation (%): 13.6 +/- 5.0 and R2: 0.95 +/- 0.02.

    CONCLUSION:

    The UIPump-system is suitable for use in PET-research for assessment of PK/PD properties by simulation of different tracer tissue kinetics in vivo.

  • 29.
    Espes, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Striated Muscle as Implantation Site for Transplanted Pancreatic Islets2011In: Journal of Transplantation, ISSN 2090-0007, E-ISSN 2090-0015, Vol. 2011, 352043- p.Article, review/survey (Refereed)
    Abstract [en]

    Islet transplantation is an attractive treatment for selected patients with brittle type 1 diabetes. In the clinical setting, intraportal transplantation predominates. However, due to extensive early islet cell death, the quantity of islets needed to restore glucose homeostasis requires in general a minimum of two donors. Moreover, the deterioration of islet function over time results in few insulin-independent patients after five-year followup. Specific obstacles to the success of islet transplantation include site-specific concerns for the liver such as the instant blood mediated inflammatory reaction, islet lipotoxicity, low oxygen tension, and poor revascularization, impediments that have led to the developing interest for alternative implantation sites over recent years. Within preclinical settings, several alternative sites have now been investigated and proven favorable in various aspects. Muscle is considered a very promising site and has physiologically properties and technical advantages that could make it optimal for islet transplantation.

  • 30.
    Espes, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Krajcovic, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Turku PET center, Faculty of Natural Sciences and Technology, Åbo Akademi, Turku, Finland.
    Quantification of Beta-Cell Mass in Intramuscular Islet Grafts using Radiolabeled Exendin-42016In: Transplantation Direct, ISSN 2373-8731, Vol. 2, no 8, e93Article in journal (Refereed)
    Abstract [en]

    Background: There is an increasing interest in alternative implantation sites to the liver for islet transplantation. Intramuscular implantation has even been tested clinically. Possibilities to monitor [beta]-cell mass would be of huge importance not only for the understanding of islet engraftment but also for the decision of changing the immunosuppressive regime. We have therefore evaluated the feasibility of quantifying intramuscular [beta]-cell mass using the radiolabeled glucagon like peptide-1 receptor agonist DO3A-VS-Cys40-Exendin-4.

    Methods: One hundred to 400 islets were transplanted to the abdominal muscle of nondiabetic mice. After 3 to 4 weeks, 0.2 to 0.5 MBq [177Lu]DO3A-VS-Cys40-Exendin-4 was administered intravenously. Sixty minutes postinjection abdominal organs and graft bearing muscle were retrieved, and the radioactive uptake measured in a well counter within 10 minutes. The specific uptake in native and transplanted islets was assessed by autoradiography. The total insulin-positive area of the islet grafts was determined by immunohistochemistry.

    Results: Intramuscular islet grafts could easily be visualized by this tracer, and the background uptake was very low. There was a linear correlation between the radioactivity uptake and the number of transplanted islets, both for standardized uptake values and the total radiotracer uptake in each graft (percentage of injected dose). The quantified total insulin area of surviving [beta] cells showed an even stronger correlation to both standardized uptake values (R = 0.96, P = 0.0002) and percentage of injected dose (R = 0.88, P = 0.0095). There was no correlation to estimated [alpha] cell mass.

    Conclusions: [177Lu]DO3A-VS-Cys40-Exendin-4 could be used to quantify [beta]-cell mass after experimental intramuscular islet transplantation. This technique may well be transferred to the clinical setting by exchanging Lutetium-177 radionuclide to a positron emitting Gallium-68.

  • 31.
    Gustafsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations2017In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, 177-186 p.Article in journal (Refereed)
    Abstract [en]

    Methods to investigate blood-brain barrier transport and pharmacologically active drug concentrations in the human brain are limited and data translation between species is challenging. Hence, there is a need to further develop the read-out of techniques like positron emission tomography ( PET) for studying neuropharmacokinetics. PET has a high translational applicability from rodents to man and measures total drug concentrations in vivo. The aim of the present study was to investigate the possibility of translating total drug concentrations, acquired through PET, to unbound concentrations, resembling those measured in the interstitial fluid by microdialysis sampling. Simultaneous PET scanning and brain microdialysis sampling were performed in rats throughout a 60 min infusion of [N-methyl-C-11] oxycodone in combination with a therapeutic dose of oxycodone and during a 60 min follow up period after the end of infusion. The oxycodone concentrations acquired with PET were converted into unbound concentrations by compensating for brain tissue binding and brain intracellular distribution, using the unbound volume of distribution in brain (Vu, brain), and were compared to microdialysis measurements of unbound concentrations. A good congruence between the methods was observed throughout the infusion. However, an accumulating divergence in the acquired PET and microdialysis data was apparent and became more pronounced during the elimination phase, most likely due to the passage of radioactive metabolites into the brain. In conclusion, the study showed that PET can be used to translate non-invasively measured total drug concentrations into unbound concentrations as long as the contribution of radiolabelled metabolites is minor or can be compensated for.

  • 32.
    Haylock, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mortensen, Anja C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Selvaraju, Ram K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Nilvebrant, Johan
    Royal Inst Technol, Sch Biotechnol, Div Prot Technol, Stockholm, Sweden.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Evaluation of a novel type of imaging probe based on a recombinant bivalent mini-antibody construct for detection of CD44v6-expressing squamous cell carcinoma2015In: International journal of oncology, ISSN 1791-2423, Vol. 48, no 2, 461-470 p.Article in journal (Refereed)
    Abstract [en]

    We have developed the CD44v6-targeting human bivalent antibody fragment AbD19384, an engineered recombinant human bivalent Fab antibody formed via dimerization of dHLX (synthetic double helix loop helix motif) domains, for potential use in antibody-based molecular imaging of squamous cell carcinoma in the head and neck region. This is a unique construct that has, to the best of our knowledge, never been assessed for molecular imaging in vivo before. The objective of the present study was to evaluate for the first time the in vitro and in vivo binding properties of radio-iodinated AbD19384, and to assess its utility as a targeting agent for molecular imaging of CD44v6-expressing tumors. Antigen specificity and binding properties were assessed in vitro. In vivo specificity and biodistribution of 125I-AbD19384 were next evaluated in tumor-bearing mice using a dual-tumor setup. Finally, AbD19384 was labeled with 124I, and its imaging properties were assessed by small animal PET/CT in tumor bearing mice, and compared with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG). In vitro studies demonstrated CD44v6-specific binding with slow off-rate for AbD19384. A favorable biodistribution profile was seen in vivo, with tumor-specific uptake. Small animal PET/CT images of 124I-AbD19384 supported the results through clearly visible high CD44v6-expressing tumors and faintly visible low expressing tumors, with superior imaging properties compared to 18F-FDG. Tumor-to-blood ratios increased with time for the conjugate (assessed up to 72 h p.i.), although 48 h p.i. proved best for imaging. Biodistribution and small-animal PET studies demonstrated that the recombinant Fab-dHLX construct AbD19384 is a promising tracer for imaging of CD44v6 antigen expression in vivo, with the future aim to be used for individualized diagnosis and early detection of squamous cell carcinomas in the head and neck region. Furthermore, this proof-of-concept research established the feasibility of using recombinant Fab-dHLX constructs for in vivo imaging of tumor biomarkers.

  • 33.
    Hellström-Lindahl, Ewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Danielsson, Angelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Czernichow, Paul
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    GPR44 is a pancreatic protein restricted to the human beta cell2016In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 53, no 3, 413-421 p.Article in journal (Refereed)
    Abstract [en]

    AIMS: To address questions regarding onset and progression of types 1 and 2 diabetes (T1D/T2D), surrogate imaging biomarkers for beta cell function and mass are needed. Here, we assess the potential of GPR44 as a surrogate marker for beta cells, in a direct comparison with clinically used biomarker VMAT2.

    METHODS: GPR44 surface availability was assessed by flow cytometry of human beta cells. RNA transcription levels in different pancreas compartments were evaluated. The density of GPR44 receptor in endocrine and exocrine tissues was assessed by the radiolabeled GPR44 ligand [(3)H]AZD 3825. A direct comparison with the established beta cell marker VMAT2 was performed by radiolabeled [(3)H]DTBZ.

    RESULTS: GPR44 was available on the cell surface, and pancreatic RNA levels were restricted to the islets of Langerhans. [(3)H]AZD 3825 had nanomolar affinity for GPR44 in human islets and EndoC-βH1 beta cells, and the specific binding to human beta cells was close to 50 times higher than in exocrine preparations. The endocrine-to-exocrine binding ratio was approximately 10 times higher for [(3)H]AZD 3825 than for [(3)H]DTBZ.

    CONCLUSION: GPR44 is a highly beta cell-specific target, which potentially offers improved imaging contrast between the human beta cell and the exocrine pancreas.

  • 34.
    Hellström-Lindahl, Ewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Ericsson, Cecilia
    AstraZeneca R&D, SE-43150 Molndal, Sweden..
    O'Mahony, Gavin
    AstraZeneca R&D, SE-43150 Molndal, Sweden..
    Johnström, Peter
    Karolinska Inst, Karolinska Univ Hosp, AstraZeneca PET Sci Ctr, Personalised Healthcare & Biomarkers, SE-17176 Stockholm, Sweden..
    Skrtic, Stanko
    AstraZeneca R&D, SE-43150 Molndal, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, SE-41345 Gothenburg, Sweden..
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Toward molecular imaging of the free fatty acid receptor 12017In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 7, 663-668 p.Article in journal (Refereed)
    Abstract [en]

    Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling. In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([H-3]AZ1, [H-3]AZ2 and [H-3]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. [H-3]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H-3]AZ2 and [H-3]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.

  • 35. Jahan, M.
    et al.
    Johnstrom, P.
    Nag, S.
    Takano, A.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Halldin, C.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Synthesis and biological evaluation of [C-11]AZ12504948; a novel tracer for imaging of glucokinase in pancreas and liver2015In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 42, no 4, 387-394 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Glucokinase (GK) is potentially a target for imaging of islets of Langerhans. Here we report the radiosynthesis and preclinical evaluation of the GK activator, [C-11]AZ12504948, for in vivo imaging of GK. Methods: [C-11]AZ12504948 was synthesized by O-methylation of the precursor, AZ125555620, using carbon-11 methyl iodide ([C-11]CH3I).Preclinical evaluation was performed by autoradiography (ARC) of human tissues and PET/CT studies in pig and non-human primate. Result: [C-11]AZ12504948 was produced in reproducible good radiochemical yield in 28-30 min. Radiochemical purity of the formulated product was >98% for up to 2 h with specific radioactivities 855 +/- 209 GBq/mu mol (n = 8). The preclinical evaluation showed some specificity for GK in liver, but not in pancreas. Conclusion:[C-11]AZ12504948 images GK in liver, but the low specificity impedes the visualization of GK in pancreas. Improved target specificity is required for further progress using PET probes based on this class of GK activators.

  • 36. Jahan, Mahabuba
    et al.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johnström, Peter
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Halldin, Christer
    Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET2011In: EJNMMI research, ISSN 2191-219X, Vol. 1, no 1, 33- p.Article in journal (Refereed)
    Abstract [en]

    Background

    Fluorine-18 dihydrotetrabenazine [DTBZ] analogues, which selectively target the vesicular monoamine transporter 2 [VMAT2], have been extensively studied for in vivo quantification of beta cell mass by positron-emission tomography [PET]. This study describes a novel deuterated radioligand [18F]fluoroethyl [FE]-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [18F]FE-DTBZ.

    Methods

    [18F]FE-DTBZ-d4 was synthesized by alkylation of 9-O-desmethyl-(+)-DTBZ precursor with deuterated [18F]FE bromide ([18F]FCD2CD2Br). Radioligand binding potential [BP] was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo pharmacokinetics and pharmacodynamics [PK/PD] was studied in a porcine model by PET/computed tomography, and the rate of defluorination was quantified by compartmental modeling.

    Results

    [18F]FE-DTBZ-d4 was produced in reproducible good radiochemical yield in 100 ± 20 min. Radiochemical purity of the formulated product was > 98% for up to 5 h with specific radioactivities that ranged from 192 to 529 GBq/μmol at the end of the synthesis. The in vitro BP for VMAT2 in the islet tissue was 27.0 ± 8.8, and for the exocrine tissue, 1.7 ± 1.0. The rate of in vivo defluorination was decreased significantly (kdefluorination = 0.0016 ± 0.0007 min-1) compared to the non-deuterated analogue (kdefluorination = 0.012 ± 0.002 min-1), resulting in a six fold increase in half-life stability.

    Conclusions

    [18F]FE-DTBZ-d4 has similar PK and PD properties for VMAT2 imaging as its non-deuterated analogue [18F]FE-DTBZ in addition to gaining significantly increased stability against defluorination. [18F]FE-DTBZ-d4 is a prime candidate for future preclinical and clinical studies on focal clusters of beta cells, such as in intramuscular islet grafts.

  • 37.
    Karlsson, Filip
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antonodimitrakis, Pantelis Clewemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Systematic screening of imaging biomarkers for the Islets of Langerhans, among clinically available positron emission tomography tracers2015In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 42, no 10, 762-769 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Functional imaging could be utilized for visualizing pancreatic islets of Langerhans. Therefore, we present a stepwise algorithm for screening of clinically available positron emission tomography (PET) tracers for their use in imaging of the neuroendocrine pancreas in the context of diabetes. Methods: A stepwise procedure was developed for screening potential islet imaging agents. Suitable PET-tracer candidates were identified by their molecular mechanism of targeting. Clinical abdominal examinations were retrospectively analyzed for pancreatic uptake and retention. The target protein localization in the pancreas was assessed in silico by -omics approaches and the in vitro by binding assays to human pancreatic tissue. Results: Six putative candidates were identified and screened by using the stepwise procedure. Among the tested PET tracers, only [C-11]5-Hydroxy-tryptophan passed all steps. The remaining identified candidates were falsified as candidates and discarded following in silico and in vitro screening. Conclusions: Of the six clinically available PET tracers identified, [C-11]5-HTP was found to be a promising candidate for beta cell imaging, based on intensity of in vivo pancreatic uptake in humans, and islet specificity as assessed on human pancreatic cell preparations. The flow scheme described herein constitutes a methodology for evaluating putative islet imaging biomarkers among clinically available PET tracers.

  • 38.
    Lahesmaa, M.
    et al.
    Univ Turku, Turku PET Ctr, Turku, Finland.;Turku Univ Hosp, Turku PET Ctr, Turku, Finland..
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Univ Turku, Turku PET Ctr, Turku, Finland..
    Oikonen, V.
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Bucci, M.
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Hirvonen, J.
    Univ Turku, Turku PET Ctr, Turku, Finland.;Univ Turku, Dept Radiol, Turku, Finland..
    Lahdenpohja, S.
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Koskensalo, K.
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Haaparanta-Solin, M.
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Virtanen, K. A.
    Univ Turku, Turku PET Ctr, Turku, Finland.;Turku Univ Hosp, Turku PET Ctr, Turku, Finland..
    Nuutila, P.
    Univ Turku, Turku PET Ctr, Turku, Finland.;Turku Univ Hosp, Dept Endocrinol, Turku, Finland..
    Cannabinoid CB1 receptors in human brown adipose tissue during cold exposure2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, S50-S50 p.Article in journal (Refereed)
  • 39. Nalin, Lovisa
    et al.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Berglund, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Andréasson, Susanne
    Wikstrand, Anna
    Rydén, Anneli
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Kandeel, Fouad
    Nyman, Görel
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Jensen-Waern, Marianne
    Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no 9, 1800-1810 p.Article in journal (Refereed)
    Abstract [en]

    Purpose

    The glucagon-like peptide-1 receptor (GLP-1R) has been proposed as a target for molecular imaging of beta cells. The feasibility of non-invasive imaging and quantification of GLP-1R in pancreas using the positron emission tomography (PET) tracer [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in non-diabetic and streptozotocin (STZ)–induced diabetic pigs treated with insulin was investigated.

    Methods

    Non-diabetic (n = 4) and STZ-induced diabetic pigs (n = 3) from the same litter were examined. Development of diabetes was confirmed by blood glucose values, clinical examinations and insulin staining of pancreatic sections post mortem. Tissue perfusion in the pancreas and kidneys was evaluated by [15O]water PET/computed tomography (CT) scans. The in vivo receptor specificity of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 was assessed by administration of either tracer alone or by competition with 3–6.5 μg/kg of Exendin-4. Volume of distribution and occupancy in the pancreas were quantified with a single tissue compartment model.

    Results

    [15O]water PET/CT examinations showed reduced perfusion in the pancreas and kidneys in diabetic pigs. [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 uptake in the pancreas of both non-diabetic and diabetic pigs was almost completely abolished by co-injection of unlabeled Exendin-4 peptide. [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 uptake did not differ between non-diabetic and diabetic pigs. In all animals, administration of the tracer resulted in an immediate increase in the heart rate (HR).

    Conclusion

    Pancreatic uptake of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 was not reduced by destruction of beta cells in STZ-induced diabetic pigs.

  • 40.
    Rydén, Anneli
    et al.
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
    Nyman, Gorel
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
    Nalin, Lovisa
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
    Andreasson, Susanne
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Jensen-Waern, Marianne
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, POB 7054, S-75007 Uppsala, Sweden..
    Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs2016In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 43, no 7, 397-402 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Radiolabeled Exendin-4, a synthetic glucagon-like peptide-1 (GLP-1) analog, is used as a tracer for diagnostic purposes of beta-cells and in experimental animal research. Exendin-4 can be radiolabeled with Ga-68, I-111 n or (99)mTc and used for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging to diagnose insulinomas, visualization of pancreatic beta-cell mass and transplanted Islets of Langerhans. In humans, Exendin-4 is widely used as a therapeutic agent for treatment of type 2 diabetes (T2D). The compound, which is administered subcutaneously (SC) may cause nausea, vomiting and a minor increase in the heart rate (HR). However, possible side-effects on cardiovascular functions after intravenous (IV) administration have not been reported. This study describes the Exendin-4 dose at which cardiovascular side-effects occur in pigs and cynomolgus monkeys. The IV effect of the tracer on insulin secretion is also investigated in pigs. Methods: Seven clinically healthy littermate pigs (40 days old) were used; three of them were made diabetic by streptozotocin (STZ). All pigs underwent PET imaging under general anesthesia to examine the glucagon-like peptide-1 receptor (GLP-1R) in beta-cells with radiolabeled Exendin-4. A baseline tracer dose IV [Ga-68]Exendin-4 (0.025 +/- 0.010 mu g/kg) followed by a competition dose IV [Ga-68]Exendin-4 (3.98 +/- 133 mu g/kg) 60 min later were administered. Blood samples were taken and analyzed for insulin secretion by using ELISA. Cardiovascular and respiratory variables were monitored throughout the experiment. Results: Immediately after administration of the high dose [Ga-68]Exendin-4 the HR rose from 122 14 to 227 +/- 40 bpm (p < 0.01) and from 100 +/- 5 to 181 +/- 13 bpm (p < 0.01) in healthy non -diabetic and diabetes-induced pigs, respectively. The tachycardia was observed for >2 h and one healthy non-diabetic pig suffered cardiac arrest 3 h after the IV [Ga-68]Exendin-4. Arrhythmia was detected by listening to the heart with a stethoscope up to 4 days after the [Ga-68]Exendin-4 injection. In all animals, no effect on the cardiovascular system was registered after the low dose of IV [Ga-68]Exendin-4. Insulin secretion increased (p < 0.05) when IV [Ga-68]Exendin-4 was given in dosages >= 0.14 mu g/kg. Conclusions: Intravenous administration of mu g/kg [Ga-68]Exendin-4 resulted in severe tachycardia and arrhythmias in healthy non -diabetic and diabetes-induced pigs, and the insulin secretion was stimulated in healthy non diabetic animals when >= 0.14 mu g/kg [Ga-68]Exendin-4 was given.

  • 41.
    Selvaraju, Ram K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wu, Zhanhong
    Todorov, Ivan
    Shively, Jack
    Kandeel, Fouad
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    In Vivo Imaging of the Glucagonlike Peptide 1 Receptor in the Pancreas with Ga-68-Labeled DO3A-Exendin-42013In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 8, 1458-1463 p.Article in journal (Refereed)
    Abstract [en]

    The glucagonlike peptide 1 receptor (GLP-1R) is mainly expressed on beta-cells in the Wets of Langerhans and is therefore an attractive target for imaging of the beta-cell mass. In the present study, Ga-68-labeled exendin-4 was evaluated for PET imaging and quantification of GLP-1R in the pancreas. Methods: Dose escalation studies of Ga-68-labeled 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl (DO3A)-exendin-4 were performed in rats (organ distribution) and cynomolgus monkeys (PET/CT imaging) to determine the GLP-1R-specific tissue uptake in vivo. Pancreatic uptake (as determined by organ distribution) in healthy rats was compared with that in diabetic rats. GLP-1R occupancy in the cynomolgus pancreas was quantified with a 1-tissue-compartment model. Results: In rodents, uptake in the pancreas was decreased from the baseline by up to 90% (P < 0.0001) by coadministration of DO3A-exendin-4 at 100 mu g/kg. Pancreatic uptake in diabetic animals was decreased by more than 80% (P < 0.001) compared with that in healthy controls, as measured by organ distribution. GLP-1R occupancy in the cynomolgus pancreas after coinjection of DO3A-exendin-4 at 0.15-20 mu g/kg ranged from 49% to 97%, as estimated by compartment modeling. Conclusion: These results strongly support the notion that Ga-68-DO3A-exendin-4 uptake in the pancreas is mediated by specific receptor binding. In addition, pancreatic uptake was decreased by selective destruction of beta-cells. This result suggests that GLP-1R can be quantified in vivo, which has major implications for the prospect of imaging of native beta-cells.

  • 42.
    Selvaraju, Ram Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Nalin, L.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Berglund, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Andreasson, S.
    Wikstrand, A.
    Ryden, A.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kandeel, F.
    Nyman, G.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jensen-Waern, M.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Positron Emission Tomography imaging of the glucagon like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, S394-S394 p., P128Article in journal (Other academic)
  • 43.
    Selvaraju, Ram Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Nalin, Lovisa
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Berglund, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Ryden, Anneli
    Kandeel, Fouad
    Nyman, Gorel
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Jensen-Waern, Marianne
    PET imaging of the GLP-1 receptor in healthy and streptozotocin-induced diabetic pigs2014In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no Suppl. 1, 387- p.Article in journal (Refereed)
  • 44.
    Selvaraju, Ram Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Todorov, I.
    Wu, Z.
    Shively, J.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kandeel, F.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Pancreatic uptake of [68Ga]DO3A-Exendin4 is mediated by the GLP-1 receptor2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no S2, S195-S195 p.Article in journal (Other academic)
  • 45.
    Selvaraju, Ram Kumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Dosimetry of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in rat, non-human primate and human2014In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no Suppl. 1Article in journal (Refereed)
  • 46.
    Spiegelberg, Diana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mortensen, Anja C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model.2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, no 5, 974-982 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition.

    METHODS: Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 × 50 mg/kg), and were imaged with PET using either (18)F-FDG or (124)I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining.

    RESULTS: AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with (124)I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with (124)I-AbD19384 as well as (18)F-FDG uptake, were not significantly altered by AT13387 treatment.

    CONCLUSION: We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues.

  • 47.
    Spiegelberg, Diana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mortensen, Anja C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Scott, A.
    Olivia Newton John Canc Res Inst, Ludwig Inst Canc Res, Melbourne, Vic, Australia.;La Trobe Univ, Melbourne, Vic, Australia..
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Molecular imaging of EGFR and EGFRvIII for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, no S1, S263-S264 p.Article in journal (Other academic)
  • 48.
    Strand, Joanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Abrahmsen, L.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gallium-68-labeled affibody molecule for PET imaging of PDGFR beta expression in vivo2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, S262-S262 p., OP469Article in journal (Other academic)
  • 49.
    Strand, Joanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Rudbecklaboratoriet.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Abrahmsen, Lars
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gallium-68-Labeled Affibody Molecule for PET Imaging of PDGFRβ Expression in Vivo2014In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 11, 3957-3964 p.Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor involved, for example, in angiogenesis. Overexpression and excessive signaling of PDGFRβ has been observed in multiple malignant tumors and fibrotic diseases, making this receptor a pharmaceutical target for monoclonal antibodies and tyrosine kinase inhibitors. Successful targeted therapy requires identification of responding patients. Radionuclide molecular imaging would enable determination of the PDGFRβ status in all lesions using a single noninvasive repeatable procedure. Recently, we have demonstrated that the affibody molecule Z09591 labeled with 111In can specifically target PDGFRβ-expressing tumors in vivo. The use of positron emission tomography (PET) as an imaging technique would provide superior resolution, sensitivity, and quantitation accuracy. In this study, a DOTA-conjugated Z09591 was labeled with the generator-produced positron emitting radionuclide 68Ga (T1/2 = 67.6 min, Eβ + max = 1899 keV, 89% β+). 68Ga-DOTA-Z09591 retained the capacity to specifically bind to PDGFRβ-expressing U-87 MG glioma cells. The half-maximum inhibition concentration (IC50) of 68Ga-DOTA-Z09591 (6.6 ± 1.4 nM) was somewhat higher than that of 111In-DOTA-Z09591 (1.4 ± 1.2 nM). 68Ga-DOTA-Z09591 demonstrated specific (saturable) targeting of U-87 MG xenografts in immunodeficient mice. The tumor uptake at 2 h after injection was 3.7 ± 1.7% IA/g, which provided a tumor-to-blood ratio of 8.0 ± 3.1. The only organ with higher accumulation of radioactivity was the kidney. MicroPET imaging provided high-contrast imaging of U-87 MG xenografts. In conclusion, the 68Ga-labeled affibody molecule Z09591 is a promising candidate for further development as a probe for imaging PDGFRβ expression in vivo using PET.

  • 50.
    Syvänen, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Blomquist, Gunnar
    Sprycha, Margareta
    Höglund, A. Urban
    Roman, Magnus
    Eriksson, Olof
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET2006In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 32, no 3, 1134-1141 p.Article in journal (Refereed)
    Abstract [en]

    Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [C-11]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [C-11]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [C-11]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [C-11]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [C-11]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [C-11]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.

12 1 - 50 of 62
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf