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  • 1.
    Bjerketorp, Joakim
    et al.
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Levenfors, Jolanta J
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Sahlberg, Christer
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Nord, Christina L
    Swedish Univ Agr Sci, Uppsala, Sweden; Medivir AB, Huddinge, Sweden.
    Andersson, Pierre F
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Guss, Bengt
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Öberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Ultupharma AB, Uppsala, Sweden.
    Broberg, Anders
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Antibacterial 3,6-Disubstituted 4-Hydroxy-5,6-dihydro-2H-pyran-2-ones from Serratia plymuthica MF371-22017In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 80, no 11, p. 2997-3002Article in journal (Refereed)
    Abstract [en]

    Bioassay-guided fractionation of culture extracts of Serratia plymuthica strain MF371-2 resulted in the isolation of two new antibacterial compounds with potent activity against Gram-positive bacteria, including Staphylococcus aureus LMG 15975 (MRSA). A spectroscopic investigation, in combination with synthesis, enabled the characterization of the compounds as 3-butyryl-4-hydroxy-6-heptyl-5,6-dihydro2H-pyran-2-one (plymuthipyranone A, 1) and 3-butyry1-4-hydroxy-6-nony1-5,6-dihydro-2H-pyran-2-one (plymuthipyranone B, 2). The MIC values for 1 and 2 against S. aureus LMG 15975 were determined to be 1-2 mu g mL(-1) and 0.8 mu g mL(-1), respectively. Compound 2 was found to have potent activity against many strains of S. aureus, including several mupirocin-resistant strains, other species of Staphylococcus, and vancomycin-resistant enterococci. Compound 2 was slightly cytotoxic for human cells, with CC50 values between 4.7 and 40 mu g mL(-1), but the CC50/MIC ratio was >= 10 for many tested combinations of human cells and bacteria, suggesting its possible use as an antibacterial agent. Several analogues were synthesized with different alkyl groups in the 3- and 6-positions (6-13), and their biological properties were evaluated. It was concluded that the activity of the compounds increased with the lengths of the alkyl and acyl substituents.

  • 2. Chiotis, K
    et al.
    Saint-Aubert, L
    Rodriguez-Vieitez, E
    Leuzy, A
    Almkvist, O
    Savitcheva, I
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Nordberg, A
    Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 7, p. 1666-1673Article in journal (Refereed)
    Abstract [en]

    The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [(18)F]THK5317 (tau deposition) and [(18)F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [(11)C]PIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [(18)F]THK5317 retention over time, in contrast to significant decreases in [(18)F]FDG uptake in temporoparietal areas. The pattern of changes in [(18)F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [(18)F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [(18)F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [(11)C]PIB scan, high [(18)F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [(18)F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.Molecular Psychiatry advance online publication, 16 May 2017; doi:10.1038/mp.2017.108.

  • 3.
    Chow, Shiao Y.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Low-Pressure Radical 11C-Aminocarbonylation of Alkyl Iodides through Thermal Initiation2017In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2017, no 8, p. 1236-1236Article in journal (Refereed)
  • 4.
    Coenen, Heinz H.
    et al.
    Res Ctr Julich, Julich, Germany.
    Gee, Antony D.
    Kings Coll London, London, England.
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY 11973 USA.
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan.
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea.
    Mach, Robert H.
    Univ Penn, Philadelphia, PA 19104 USA.
    Mindt, Thomas L.
    Univ Vienna, Vienna, Austria.
    Pike, Victor W.
    NIMH, Bethesda, MD 20892 USA.
    Windhorst, Albert D.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
    International Consensus Radiochemistry Nomenclature Guidelines2018In: Radiochimica Acta, ISSN 0033-8230, E-ISSN 2193-3405, Vol. 106, no 7, p. 623-625Article in journal (Other academic)
  • 5.
    Coenen, Heinz H.
    et al.
    Forschungszentrum Julich, Julich, Germany..
    Gee, Antony D.
    Kings Coll London, London, England..
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY 11973 USA..
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan..
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea..
    Mach, Robert H.
    Univ Penn, Philadelphia, PA 19104 USA..
    Mindt, Thomas L.
    Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria..
    Pike, Victor W.
    NIMH, Bethesda, MD 20892 USA..
    Windhorst, Albert D.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands..
    Letter to the Editor: International Consensus Radiochemistry Nomenclature Guidelines2018In: Current Radiopharmaceuticals, ISSN 1874-4710, E-ISSN 1874-4729, Vol. 11, no 1, p. 73-75Article in journal (Other academic)
  • 6.
    Coenen, Heinz H.
    et al.
    Res Ctr Julich, Julich, Germany.
    Gee, Antony D.
    Kings Coll London, London, England.
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY USA.
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan.
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea.
    Mach, Robert H.
    Univ Penn, Philadelphia, PA USA.
    Mindt, Thomas L.
    Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria.
    Pike, Victor W.
    NIMH, Bethesda, MD USA.
    Windhorst, Albert D.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands.
    Open letter to journal editors on: international consensus radiochemistry nomenclature guidelines2018In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 8, no 1, p. 70-72Article in journal (Other academic)
  • 7.
    Coenen, Heinz H.
    et al.
    Res Ctr Julich, Julich, Germany.
    Gee, Antony D.
    Kings Coll London, London, England.
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY USA.
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan.
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea.
    Mach, Robert H.
    Univ Penn, Philadelphia, PA USA.
    Mindt, Thomas L.
    Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria.
    Pike, Victor W.
    NIMH, Bethesda, MD USA.
    Windhorst, Albert D.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
    Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines2018In: Nuclear medicine communications, ISSN 0143-3636, E-ISSN 1473-5628, Vol. 39, no 3, p. 193-195Article in journal (Other academic)
  • 8.
    Coenen, Heinz H.
    et al.
    Res Ctr Jülich, Jülich, Germany.
    Gee, Antony D.
    Kings Coll London, London, England..
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY USA.
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan.
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea.
    Mach, Robert H.
    Univ Penn, Philadelphia, PA USA.
    Mindt, Thomas L.
    Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria.
    Pike, Victor W.
    NIMH, Bethesda, MD USA.
    Windhorst, Albert D.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
    Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines2018In: Annals of Nuclear Medicine, ISSN 0914-7187, E-ISSN 1864-6433, Vol. 32, no 3, p. 236-238Article in journal (Other academic)
  • 9.
    Coenen, Heinz H.
    et al.
    Res Ctr Julich, Julich, Germany.
    Gee, Antony D.
    Kings Coll London, London, England.
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY, USA.
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan.
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea.
    Mach, Robert H.
    Univ Penn, Philadelphia, PA, USA.
    Mindt, Thomas L.
    Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria.
    Pike, Victor W.
    NIMH, Bethesda, MD, USA.
    Windhorst, Albert D.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands.
    Open letter to journal editors on: international consensus radiochemistry nomenclature guidelines2018In: Journal of Radioanalytical and Nuclear Chemistry, ISSN 0236-5731, E-ISSN 1588-2780, Vol. 315, no 3, p. 443-445Article in journal (Other academic)
  • 10.
    Coenen, Heinz H.
    et al.
    Res Ctr Julich, Julich, Germany..
    Gee, Antony D.
    Kings Coll London, London, England..
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY 11973 USA..
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan..
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea..
    Mach, Robert H.
    Univ Penn, Philadelphia, PA 19104 USA..
    Mindt, Thomas L.
    Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria..
    Pike, Victor W.
    NIMH, Bethesda, MD 20892 USA..
    Windhorst, Albert D.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands..
    Open letter to journal editors on: International consensus radiochemistry nomenclature guidelines2018In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 61, no 4, p. 402-404Article in journal (Other academic)
  • 11.
    Coenena, Heinz H.
    et al.
    Forschungszentrum Julich, Julich, Germany.
    Gee, Antony D.
    Kings Coll London, London, England.
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY USA.
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan.
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea.
    Mach, Robert H.
    Univ Penn, Philadelphia, PA USA.
    Mindt, Thomas L.
    Univ Vienna, Vienna, Austria.
    Pike, Victor W.
    NIH, Bldg 10, Bethesda, MD USA.
    Windhorst, Albert D.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands.
    International Consensus Radiochemistry Nomenclature Guidelines2018In: Nuclearmedizin, ISSN 0029-5566, Vol. 57, no 1, p. 40-41Article in journal (Refereed)
  • 12.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin42017In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 11, p. 1039-1045Article in journal (Refereed)
    Abstract [en]

    AIMS: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed.

    METHODS: -Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment.

    RESULTS: -Exendin4.

    CONCLUSIONS: IPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP-1R as an imaging biomarker for pancreatic beta cells.

  • 13.
    Eriksson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab. Antaros Med AB, Uppsala, Sweden.
    Bossart, M.
    Sanofi Aventis, Frankfurt, Germany..
    Haack, T.
    Sanofi Aventis, Frankfurt, Germany..
    Laitinen, I.
    Sanofi Aventis, Frankfurt, Germany..
    Larsen, P.
    Sanofi Aventis, Frankfurt, Germany..
    Plettenburg, O.
    Helmholtz Zentrum, Munich, Germany..
    Johansson, L.
    Antaros Med AB, Molndal, Sweden..
    Pierrou, S.
    Antaros Med AB, Molndal, Sweden..
    Wagner, M.
    Sanofi Aventis, Frankfurt, Germany..
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala PET Ctr, Uppsala, Sweden..
    First-in-class PET tracer for the glucagon receptor2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S400-S400Article in journal (Other academic)
  • 14.
    Fani, Melpomeni
    et al.
    Division of Radiopharmaceutical Chemistry, University Hospital of Basel, 4031 Basel, Switzerland.
    Peitl, Petra Kolenc
    Department of Nuclear Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms2017In: Pharmaceuticals, ISSN 1424-8247, E-ISSN 1424-8247, Vol. 10, no 1, article id E30Article, review/survey (Refereed)
    Abstract [en]

    Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.

  • 15.
    Gonzalez, Miguel A. Cortes
    et al.
    Stockholm Univ, Dept Organ Chem, SE-10691 Stockholm, Sweden.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Gomez, Antonio Bermejo
    Stockholm Univ, Dept Organ Chem, SE-10691 Stockholm, Sweden;Karolinska Inst, AstraZeneca PET Ctr, SE-17176 Stockholm, Sweden.
    Meyer, Denise N.
    Stockholm Univ, Dept Organ Chem, SE-10691 Stockholm, Sweden.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Schou, Magnus
    Karolinska Inst, AstraZeneca PET Ctr, SE-17176 Stockholm, Sweden.
    Szabo, Kalman J.
    Stockholm Univ, Dept Organ Chem, SE-10691 Stockholm, Sweden.
    [18F]fluoro-benziodoxole: a no-carrier-added electrophilic fluorinating reagent. Rapid, simple radiosynthesis, purification and application for fluorine-18 labelling2018In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 54, no 34, p. 4286-4289Article in journal (Refereed)
    Abstract [en]

    Operationally simple radiosynthesis and purification of [F-18]fluoro-benziodoxole was developed starting from a cyclotron produced [F-18]F- precursor, [F-18]TBAF, and tosyl-benziodoxole. The synthetic utility of [F-18]fluoro-benziodoxole was demonstrated by electrophilic fluorocyclization of o-styrilamides proceeding with high RCC (typically 50-90%) and high molar activity (up to 396 GBq mol(-1)).

  • 16.
    Hulsart Billström, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bergman, Kristoffer
    TERMIRA, Stockholm, Sweden.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 285, p. 178-186Article in journal (Refereed)
    Abstract [en]

    Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.

  • 17.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Chiotis, Konstantinos
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Leuzy, Antoine
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Nordberg, Agneta
    Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PETManuscript (preprint) (Other academic)
  • 18.
    Kero, Tanja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sorensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Wilking, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Vedin, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Rosengren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wikstrom, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Quantification of (11)C-PIB kinetics in cardiac amyloidosis2018In: Journal of Nuclear Cardiology, ISSN 1071-3581, EISSN 1532-6551Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The purpose of this work was to determine the optimal tracer kinetic model of (11)C-PIB and to validate the use of the simplified methods retention index (RI) and standardized uptake value (SUV) for quantification of cardiac (11)C-PIB uptake in amyloidosis. METHODS AND RESULTS: Single-tissue, reversible and irreversible two-tissue models were fitted to data from seven cardiac amyloidosis patients who underwent (11)C-PIB PET scans and arterial blood sampling for measurement of blood radioactivity and metabolites. The irreversible two-tissue model (2Tirr) best described cardiac (11)C-PIB uptake. RI and SUV showed high correlation with the rate of irreversible binding (Ki) from the 2Tirr model (r(2 )=0.95 and r(2 )=0.94). Retrospective data from 10 amyloidosis patients and 5 healthy controls were analyzed using RI, SUV, as well as compartment modelling with a population-average metabolite correction. All measures were higher in amyloidosis patients than in healthy controls (p=.001), but with an overlap between groups for Ki. CONCLUSION: An irreversible two-tissue model best describes the (11)C-PIB uptake in cardiac amyloidosis. RI and SUV correlate well with Ki from the 2Tirr model. RI and SUV discriminate better between amyloidosis patients and controls than Ki based on population-average metabolite correction.

  • 19.
    Ladds, Marcus J. G. W.
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    van Leeuwen, Ingeborg M. M.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Drummond, Catherine J.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Chu, Su
    Comprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA..
    Healy, Alan R.
    Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland..
    Popova, Gergana
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Fernandez, Andres Pastor
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Mollick, Tanzina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    Darekar, Suhas
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    Sedimbi, Saikiran K.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Nekulova, Marta
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic..
    Sachweh, Marijke C. C.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Campbell, Johanna
    Univ Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland..
    Higgins, Maureen
    Univ Dundee, Ctr Oncol & Mol Med, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Tayside, Scotland..
    Tuck, Chloe
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Popa, Mihaela
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway..
    Safont, Mireia Mayoral
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway..
    Gelebart, Pascal
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway..
    Fandalyuk, Zinayida
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway..
    Thompson, Alastair M.
    Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Holcombe Blvd, Houston, TX 77030 USA..
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gustavsson, Anna-Lena
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17121 Stockholm, Sweden..
    Johansson, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17121 Stockholm, Sweden..
    Farnegardh, Katarina
    Sci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden..
    Yngve, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Saleh, Aljona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Haraldsson, Martin
    Sci Life Lab, Drug Discovery & Dev Platform, Tomtebodavagen 23, SE-17121 Solna, Sweden..
    D'Hollander, Agathe C. A.
    Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland..
    Franco, Marcela
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Zhao, Yan
    Newcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England..
    Hakansson, Maria
    SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden..
    Walse, Bjorn
    SARomics Biostruct, Medicon Village, SE-22381 Lund, Sweden..
    Larsson, Karin
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Peat, Emma M.
    Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland..
    Pelechano, Vicent
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    Lunec, John
    Newcastle Univ, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle NE1 7RU, England..
    Vojtesek, Borivoj
    Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno 65653, Czech Republic..
    Carmena, Mar
    Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland..
    Earnshaw, William C.
    Univ Edinburgh, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland..
    McCarthy, Anna R.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Westwood, Nicholas J.
    Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland.;Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland.;EaStCHEM, St Andrews KY16 9ST, Fife, Scotland..
    Arsenian-Henriksson, Marie
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden..
    Lane, David P.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    Bhatia, Ravi
    Comprehens Canc Ctr, Div Hematol & Oncol, 1720 2nd Ave South,NP2540, Birmingham, AL 35294 USA..
    McCormack, Emmet
    Univ Bergen, Dept Clin Sci, Hematol Sect, Ctr Canc Biomarkers,CCBIO, N-5021 Bergen, Norway.;Haukeland Hosp, Haematol Sect, Dept Med, Bergen, Norway..
    Lain, Sonia
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SE-17177 Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, SciLifeLab, Tomtebodavagen 23, SE-17121 Stockholm, Sweden..
    A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1107Article in journal (Refereed)
    Abstract [en]

    The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

  • 20.
    Lindström, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Trampal, Carlos
    Lindsjö, Lars
    Ilan, Ezgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Medical Physics, Uppsala University Hospital, Uppsala, Sweden .
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. PET Centre, Uppsala University Hospital, Uppsala, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Medical Physics, Uppsala University Hospital, Uppsala, Sweden .
    Evaluation of penalized likelihood estimation reconstruction on a digital time-of-flight PET/CT scanner for 18F-FDG whole-body examinations2018In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 7, p. 1152-1158Article in journal (Refereed)
    Abstract [en]

    The resolution and quantitative accuracy of PET are highly influenced by the reconstruction method. Penalized-likelihood estimation algorithms allow for fully convergent iterative reconstruction, generating a higher image contrast than ordered-subsets expectation maximization (OSEM) while limiting noise. In this study, a type of penalized reconstruction known as block-sequential regularized expectation maximization (BSREM) was compared with time-of-flight OSEM (TOF OSEM). Various strengths of noise penalization factor β were tested along with various acquisition durations and transaxial fields of view (FOVs) with the aim of evaluating the performance and clinical use of BSREM for 18F-FDG PET/CT, both quantitatively and in a qualitative visual evaluation. Methods: Eleven clinical whole-body 18F-FDG PET/CT examinations acquired on a digital TOF PET/CT scanner were included. The data were reconstructed using BSREM with point-spread function recovery and β-factors of 133, 267, 400, and 533—and using TOF OSEM with point-spread function—for various acquisition times per bed position and various FOVs. Noise level, signal-to-noise ratio (SNR), signal-to-background ratio (SBR), and SUV were analyzed. A masked evaluation of visual image quality, rating several aspects, was performed by 2 nuclear medicine physicians to complement the analysis. Results: The lowest levels of noise were reached with the highest β-factor, resulting in the highest SNR, which in turn resulted in the lowest SBR. A β-factor of 400 gave noise equivalent to TOF OSEM but produced a significant increase in SUVmax (11%), SNR (22%), and SBR (12%). BSREM with a β-factor of 533 at a decreased acquisition duration (2 min/bed position) was comparable to TOF OSEM at a full acquisition duration (3 min/bed position). Reconstructed FOV had an impact on BSREM outcome measures; SNR increased and SBR decreased when FOV was shifted from 70 to 50 cm. The evaluation of visual image quality resulted in similar scores for reconstructions, although a β-factor of 400 obtained the highest mean whereas a β-factor of 267 was ranked best in overall image quality, contrast, sharpness, and tumor detectability. Conclusion: In comparison with TOF OSEM, penalized BSREM reconstruction resulted in an increased tumor SUVmax and an improved SNR and SBR at a matched level of noise. BSREM allowed for a shorter acquisition than TOF OSEM, with equal image quality.

  • 21.
    Monazzam, Azita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Razmara, Masoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 748Article in journal (Refereed)
    Abstract [en]

    Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

  • 22.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Yngve, Ulrika
    Wilking, Helena
    Gustavsson, Sven Åke
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Antoni, Gunnar
    Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS).2018In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344Article in journal (Refereed)
    Abstract [en]

    The radiosynthesis and GMP validation of [11 C]AMT for human use are described. Three consecutive batches were produced giving 940-3790 MBq (4%-17% RCY, decay corrected, based on [11 C]CO2 ) of the tracer. The molar activity at the end of synthesis was 19 to 35 GBq/μmol, the radiochemical purity was ≥98%, and the enantiomeric purity was >99%. While the synthesis method was automated using a new generation of synthesis equipment, tracer production system developed in house, the method should be readily applicable to other synthesis platforms with minor modifications.

  • 23.
    Odell, Luke R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Åkerbladh, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Schembri, Luke S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Roslin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Carbonylations beyond aryl-X: Development of new multicomponent reactions2018In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 255Article in journal (Other academic)
  • 24. Pilebro, Björn
    et al.
    Arvidsson, Sandra
    Lindqvist, Per
    Sundström, Torbjörn
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Suhr, Ole
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Positron emission tomography (PET) utilizing Pittsburgh compound B (PIB) for detection of amyloid heart deposits in hereditary transthyretin amyloidosis (ATTR)2018In: Journal of Nuclear Cardiology, ISSN 1071-3581, E-ISSN 1532-6551, Vol. 25, no 1, p. 240-248Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: DPD scintigraphy has been advocated for imaging cardiac amyloid in ATTR amyloidosis. PET utilizing (11)C-Pittsburgh compound B (PIB) is the gold standard for imaging brain amyloid in Alzheimer's disease. PIB was recently shown to identify cardiac amyloidosis in both AL and ATTR amyloidosis. In the ATTR population, two types of amyloid fibrils exist, one containing fragmented and full-length TTR (type A) and the other only full-length TTR (type B). The aim of this study was to further evaluate PIB-PET in patients with hereditary ATTR amyloidosis.

    METHODS: Ten patients with biopsy-proven V30M ATTR amyloidosis and discrete or no signs of cardiac involvement were included. Patients were grouped according to TTR-fragmentation. All underwent DPD scintigraphy, echocardiography, and PIB-PET. A left ventricular PIB-retention index (PIB-RI) was established and compared to five normal volunteers.

    RESULTS: PIB-RI was increased in all patients (P < 0.001), but was significantly higher in type B than in type A (0.129 ± 0.041 vs 0.040 ± 0.006 min(-1), P = 0.009). Cardiac DPD uptake was elevated in group A and absent in group B.

    CONCLUSION: PIB-PET, in contrast to DPD scintigraphy, has the potential to specifically identify cardiac amyloid depositions irrespective of amyloid fibril composition. The heart appears to be a target organ for amyloid deposition in ATTR amyloidosis.

  • 25.
    Reddy Vanga, Sudarsana
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Ng, Leelee
    Monash Univ, Biomed Discovery Inst, Dept Physiol, Clayton, Vic 3800, Australia.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Chai, Siew Yeen
    Monash Univ, Biomed Discovery Inst, Dept Physiol, Clayton, Vic 3800, Australia.
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides2018In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 4, p. 4509-4521Article in journal (Refereed)
    Abstract [en]

    The insulin-regulated aminopeptidase (IRAP) is a membrane-bound zinc metallopeptidase with many important regulatory functions. It has been demonstrated that inhibition of IRAP by angiotensin IV (Ang IV) and other peptides, as well as more druglike inhibitors, improves cognition in several rodent models. We recently reported a series of aryl sulfonamides as small-molecule IRAP inhibitors and a promising scaffold for pharmacological intervention. We have now expanded with a number of derivatives, report their stability in liver microsomes, and characterize the activity of the whole series in a new assay performed on recombinant human IRAP. Several compounds, such as the new fluorinated derivative 29, present submicromolar affinity and high metabolic stability. Starting from the two binding modes previously proposed for the sulfonamide scaffold, we systematically performed molecular dynamics simulations and binding affinity estimation with the linear interaction energy method for the full compound series. The significant agreement with experimental affinities suggests one of the binding modes, which was further confirmed by the excellent correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations. The new experimental data and the computationally derived structure-activity relationship of the sulfonamide series provide valuable information for further lead optimization of novel IRAP inhibitors.

  • 26.
    Roslin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Dahl, Kenneth
    Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA; Harvard Med Sch, Dept Radiol, Boston, MA USA.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Reaction of 11C‐benzoyl chlorides with metalloid reagents: 11C‐labeling of benzyl alcohols, benzaldehydes, and phenylketones from [11C]CO2018In: Journal of Labelled Compounds and Radiopharmaceuticals, ISSN 0362-4803, Vol. 61, no 5, p. 447-454Article in journal (Refereed)
    Abstract [en]

    In this article, we describe the carbon‐11 (11C, t1/2 = 20.4 minutes) labeling of benzyl alcohols, benzaldehydes, and ketones using an efficient 2-€step synthesis in which 11C-€carbon monoxide is used in an initial palladium-€mediated reaction to produce 11C-€benzoyl chloride as a key intermediate. In the second step, the obtained 11C-€benzoyl chloride is further treated with a metalloid reagent to furnish the final 11C-€labeled product. Benzyl alcohols were obtained in moderated to high non‐isolated radiochemical yields (RCY, 35%-90%) with lithium aluminum hydride or lithium aluminum deuteride as metalloid reagent. Changing the metalloid reagent to either tributyltin hydride or sodium borohydride, allowed for the reliable syntheses of 11C-€benzaldehydes in RCYs ranging from 58% to 95%. Finally, sodium tetraphenylborate were utilized to obtain 11C-€phenyl ketones in high RCYs (77%-95%). The developed method provides a new and efficient route to 3 different classes of compounds starting from aryl iodides or aryl bromides.

  • 27.
    Roy, Tamal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Rydfjord, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Palladium-catalyzed carbonylation of aryl bromides using microwave heating and bis[CP-Fe(II)-(CO)2] as a carbon monoxide source2018In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 59, no 13, p. 1230-1232Article in journal (Refereed)
    Abstract [en]

    A palladium-catalyzed, microwave assisted carbonylative reaction is described for the synthesis of benzamides from aryl bromides and primary or secondary amines. The developed method uses bis(cyclopentadienyldicarbonyliron) as a solid source of carbon monoxide to produce a diverse set of secondary and tertiary amides in 42-82% yield.

  • 28. Verbeek, Joost
    et al.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Huisman, Marc
    Schuit, Robert C
    Molthoff, Carla F M
    Voskuyl, Rob A
    de Lange, Elizabeth C
    Lammertsma, Adriaan A
    Windhorst, Albert D
    Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([18F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression.2018In: EJNMMI radiopharmacy and chemistry, ISSN 2365-421X, Vol. 3, article id 11Article in journal (Refereed)
    Abstract [en]

    Background: Several P-glycoprotein (P-gp) substrate tracers are available to assess P-gp function in vivo, but attempts to develop a tracer for measuring expression levels of P-gp have not been successful. Recently, (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide was described as a potential selective P-gp inhibitor that is not transported by P-gp. Therefore, the purpose of this study was to radiolabel two of its analogues and to assess their potential for imaging P-gp expression using PET.

    Results: [18F]2-(4-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]5) and [18F]2-(6-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]6) were synthesized and both their biodistribution and metabolism were evaluated in rats. In addition, PET scans were acquired in rats before and after tariquidar (P-gp inhibitor) administration as well as in P-gp knockout (KO) mice.Both [18F]5 and [18F]6 were synthesized in 2-3% overall yield, and showed high brain uptake in ex vivo biodistribution studies. [18F]6 appeared to be metabolically unstable in vivo, while [18F]5 showed moderate stability with limited uptake of radiolabelled metabolites in the brain. PET studies showed that transport of [18F]5 across the blood-brain barrier was not altered by pre-treatment with the P-gp inhibitor tariquidar, and uptake was significantly lower in P-gp KO than in wild-type animals and indeed transported across the BBB or bound to P-gp in endothelial cells.

    Conclusion: In conclusion, [18F]5 and [18F]6 were successfully and reproducibly synthesized, albeit with low radiochemical yields. [18F]5 appears to be a radiotracer that binds to P-gp, as showed in P-gp knock-out animals, but is not a substrate for P-gp.

  • 29.
    Wannberg, Johan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Isaksson, Rebecka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Bremberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes2018In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 3, p. 519-522Article in journal (Refereed)
    Abstract [en]

    A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.

  • 30.
    Åkerbladh, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Schembri, Luke S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Palladium(0)-Catalyzed Carbonylative One-Pot Synthesis of N-Acylguanidines2017In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, no 23, p. 12520-12529Article in journal (Refereed)
    Abstract [en]

    A convenient synthetic strategy toward N-acylguanidines via a sequential one-pot multicomponent carbonylation/amination reaction has been developed. The compounds were readily obtained via an N-cyanobenzamide intermediate formed from the Pd(0)-catalyzed carbonylative coupling of cyanamide and aryl iodides or bromides. Subsequent amination with a large variety of amines provided the final N-acylguanidines, with the overall formation of one C-C and two C-N bonds, in moderate to excellent yields. The substrate scope was found to be wide and the methodology was used to produce over 50 compounds, including 29 novel molecules. Furthermore, three separate nitrogen-containing heterocycles were prepared from the N-acylguanidines synthesized using the developed multicomponent, carbonylative method.

1 - 30 of 30
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