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Eriksson, Olof
Publications (10 of 62) Show all publications
Carlbom, L., Espes, D., Lubberink, M., Martinell, M., Johansson, L., Ahlström, H., . . . Eriksson, O. (2017). [(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes. Diabetes, 66(5), 1286-1292.
Open this publication in new window or tab >>[(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes
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2017 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 5, 1286-1292 p.Article in journal (Refereed) Published
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.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-316831 (URN)10.2337/db16-1449 (DOI)000399799800022 ()28246291 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF), K2015-54X-12219-19-4 K2013-64X-08268-26-3 K2013-55X-15043 921-2014-7054Novo NordiskSwedish Child Diabetes Foundation
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2017-05-11Bibliographically approved
Gustafsson, S., Eriksson, J., Syvänen, S., Eriksson, O., Hammarlund-Udenaes, M. & Antoni, G. (2017). Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations. NeuroImage, 155, 177-186.
Open this publication in new window or tab >>Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations
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2017 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, 177-186 p.Article in journal (Refereed) Published
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.

Keyword
Blood-brain barrier, Unbound concentration, Positron emission tomography, Microdialysis, Pharmacokinetics, Oxycodone
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-332421 (URN)10.1016/j.neuroimage.2017.04.068 (DOI)000405460900015 ()28467891 (PubMedID)
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2017-11-02Bibliographically approved
Velikyan, I., Rosenström, U. & Eriksson, O. (2017). Fully automated GMP production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 for clinical use. American Journal of Nuclear Medicine and Molecular Imaging, 7(3), 111-125.
Open this publication in new window or tab >>Fully automated GMP production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 for clinical use
2017 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, no 3, 111-125 p.Article in journal (Refereed) Published
Abstract [en]

[Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4/PET-CT targeting glucagon like peptide-1 receptor (GLP-1R) has previously demonstrated its potential clinical value for the detection of insulinomas. The production and accessibility of this radiopharmaceutical is one of the critical factors in realization of clinical trials and routine clinical examinations. Previously, the radiopharmaceutical was prepared manually, however larger scale of clinical trials and healthcare requires automation of the production process in order to limit the operator radiation dose as well as improve tracer manufacturing robustness and on-line documentation for enhanced good manufacturing practice (GMP) compliance. A method for Ga-68-labelling of DO3A-VS-Cys(40)-Exendin-4 on a commercially available synthesis platform was developed. Equipment such as Ge-68/Ga-68 generator, synthesis platform, and disposable cassettes for Ga-68-labelling used in the study was purchased from Eckert & Ziegler. DO3A-VS-Cys(40)-Exendin-4 was synthesized in-house. The parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration, pH, product purification step were investigated and optimised. Reproducible and GMP compliant automated production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 was developed. Exendin-4 comprising methionine amino acid residue was prone to oxidation which was strongly influenced by the elevated temperature, radioactivity amount, and precursor concentration. The suppression of the oxidative radiolysis was achieved by addition of ethanol, dihydroxybenzoic acid and ascorbic acid to the reaction buffer as well as by optimizing heating temperature. The non-decay corrected radiochemical yield was 43 +/- 2% with radiochemical purity of over 90% wherein the individual impurity signals in HPLC chromatogram did not exceed 5%. Automated production and quality control methods were established for paving the pathway for broader clinical use of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4.

Keyword
Exendin-4, Insulinoma, GLP-1, GMP, Gallium-68, automation
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-335532 (URN)000409370800002 ()28721305 (PubMedID)
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-08Bibliographically approved
Hellström-Lindahl, E., Åberg, O., Ericsson, C., O'Mahony, G., Johnström, P., Skrtic, S. & Eriksson, O. (2017). Toward molecular imaging of the free fatty acid receptor 1. Acta Diabetologica, 54(7), 663-668.
Open this publication in new window or tab >>Toward molecular imaging of the free fatty acid receptor 1
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2017 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 7, 663-668 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
SPRINGER-VERLAG ITALIA SRL, 2017
Keyword
FFAR1, GPR40, Beta cell imaging, Islet imaging, Drug development
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-329002 (URN)10.1007/s00592-017-0989-7 (DOI)000403508100006 ()28409274 (PubMedID)
Funder
Swedish Child Diabetes FoundationSwedish Diabetes AssociationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2017-09-06 Created: 2017-09-06 Last updated: 2017-09-06Bibliographically approved
Lahesmaa, M., Eriksson, O., Oikonen, V., Bucci, M., Hirvonen, J., Lahdenpohja, S., . . . Nuutila, P. (2016). Cannabinoid CB1 receptors in human brown adipose tissue during cold exposure. Paper presented at 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY. Diabetologia, 59, S50-S50.
Open this publication in new window or tab >>Cannabinoid CB1 receptors in human brown adipose tissue during cold exposure
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, S50-S50 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
SPRINGER, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-322045 (URN)000398373700096 ()
Conference
52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-16Bibliographically approved
Rydén, A., Nyman, G., Nalin, L., Andreasson, S., Korsgren, O., Eriksson, O. & Jensen-Waern, M. (2016). Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs. Nuclear Medicine and Biology, 43(7), 397-402.
Open this publication in new window or tab >>Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs
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2016 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 43, no 7, 397-402 p.Article in journal (Refereed) Published
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.

Keyword
Exenatide, Adverse-effects, Tachycardia, Arrhythmias, Swine, Imaging, PET, Monkeys
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-299855 (URN)10.1016/j.nucmedbio.2016.04.002 (DOI)000378760500002 ()27179248 (PubMedID)
Funder
Swedish Research Council, VR K2015-54X-12219-4Swedish Child Diabetes FoundationSwedish Diabetes Association
Available from: 2016-07-29 Created: 2016-07-28 Last updated: 2017-11-28Bibliographically approved
Velikyan, I., Rosenström, U., Eriksson, O. & Antoni, G. (2016). Ga-68/PET imaging and quantification of fibrosis using peptide-based tracers. Paper presented at Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 15-19, 2016, Barcelona, SPAIN. European Journal of Nuclear Medicine and Molecular Imaging, 43, S73-S73.
Open this publication in new window or tab >>Ga-68/PET imaging and quantification of fibrosis using peptide-based tracers
2016 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, S73-S73 p.Article in journal (Refereed) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-316227 (URN)000391801600167 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 15-19, 2016, Barcelona, SPAIN
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2017-11-29Bibliographically approved
Hellström-Lindahl, E., Danielsson, A., Pontén, F., Czernichow, P., Korsgren, O., Johansson, L. & Eriksson, O. (2016). GPR44 is a pancreatic protein restricted to the human beta cell. Acta Diabetologica, 53(3), 413-421.
Open this publication in new window or tab >>GPR44 is a pancreatic protein restricted to the human beta cell
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2016 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 53, no 3, 413-421 p.Article in journal (Refereed) Published
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.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-267945 (URN)10.1007/s00592-015-0811-3 (DOI)000376657300008 ()26467464 (PubMedID)
Funder
Swedish Diabetes AssociationSwedish Child Diabetes FoundationNIH (National Institute of Health), 2U01AI065192-06
Available from: 2015-11-30 Created: 2015-11-30 Last updated: 2017-12-01Bibliographically approved
Eriksson, O., Laughlin, M., Brom, M., Nuutila, P., Roden, M., Hwa, A., . . . Gotthardt, M. (2016). In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use. Diabetologia, 59(7), 1340-1349.
Open this publication in new window or tab >>In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 7, 1340-1349 p.Article, review/survey (Refereed) Published
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.

Keyword
Beta cell, Beta cell imaging, Diabetes, Exendin, Islet imaging, Islets of Langerhans, PET, Review, SPECT
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-300377 (URN)10.1007/s00125-016-3959-7 (DOI)000378047800002 ()27094935 (PubMedID)
Available from: 2016-08-08 Created: 2016-08-08 Last updated: 2017-11-28Bibliographically approved
Spiegelberg, D., Mortensen, A. C., Selvaraju, R. K., Eriksson, O., Stenerlöw, B. & Nestor, M. (2016). Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model.. European Journal of Nuclear Medicine and Molecular Imaging, 43(5), 974-982.
Open this publication in new window or tab >>Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model.
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2016 (English)In: 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) Published
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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-270260 (URN)10.1007/s00259-015-3260-x (DOI)000373306800020 ()26627081 (PubMedID)
Funder
Swedish Cancer Society, CAN 2012/399; CAN 2014/661Swedish Research Council, 2013-30876-104113-30
Available from: 2015-12-22 Created: 2015-12-22 Last updated: 2017-12-01Bibliographically approved
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