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Positron Emission Tomography imaging of the glucagon like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs
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 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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
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2014 (English)In: 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, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
2014. Vol. 41, no S2, S394-S394 p., P128
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-247701ISI: 000348841901124OAI: oai:DiVA.org:uu-247701DiVA: diva2:799808
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 18-22, 2014, Gothenburg, SWEDEN
Available from: 2015-03-31 Created: 2015-03-23 Last updated: 2017-12-04Bibliographically approved
In thesis
1. [68Ga]Exendin-4: Bench-to-Bedside: PET molecular imaging of the GLP-1 receptor for diabetes and cancer
Open this publication in new window or tab >>[68Ga]Exendin-4: Bench-to-Bedside: PET molecular imaging of the GLP-1 receptor for diabetes and cancer
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes epidemic is underway. Beta cell dysfunction (BCF) and loss of beta cell mass (BCM) are known to be key events in its progression. Currently, there are no reliable techniques to estimate or follow the loss of BCM, in vivo. Non-invasive imaging and quantification of the whole BCM in the pancreas, therefore, has a great potential for understanding the progression of diabetes and the scope for early diagnosis for Type 2 diabetes.

Glucagon-like peptide-1 receptor (GLP-1R) is known to be selectively expressed on the pancreatic beta cells and overexpressed on the insulinoma, a pancreatic neuroendocrine tumor (PNET). Therefore, this receptor is considered to be a selective imaging biomarker for the beta cells and the insulinoma. Exendin-4 is a naturally occurring analog of GLP-1 peptide. It binds and activates GLP-1R with same the potency and engages in the insulin synthesis, with a longer biological half-life. In this thesis, Exendin-4 precursor, DO3A-VS-Cys40-Exendin-4 labeled with [68Ga], [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 ([68Ga]Exendin-4), was evaluated in different species models, namely, immune deficient nude mice, rats, pigs, non-human primate (NHP), and clinically in one insulinoma patient by positron emission tomography (PET), for its potential in beta cell imaging and its quantification as well as for visualizing the insulinoma. From internal dosimetry, the possible number of repetitive [68Ga]Exendin-4-PET/CT scans was estimated.

Pancreatic uptake and insulinoma tumor uptake of [68Ga]Exendin-4 were confirmed to be mediated by the specific binding to the GLP-1R. Pancreatic GLP-1R could be visualized and semi-quantified, for diabetic studies, except in rats. Nonetheless, we found conflicting results regarding the GLP-1R being a selective imaging biomarker for the beta cells. PET/CT scan of the patient with [68Ga]Exendin-4 has proven to be more sensitive than the clinical neuroendocrine tracer, [11C]5-HTP, as  it could reveal small metastatic tumors in liver. The kidney was the dose-limiting organ in the entire species model, from absorbed dose estimation. Before reaching a yearly kidney limiting dose of 150 mGy and a whole body effective dose of 10 mSv, 2–4 [68Ga]Exendin-4 PET/CT scans be performed in an adult human, which enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma, as well as in healthy volunteers enrolled in the early phase of anti-diabetic drug development studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 202
Keyword
PET, [68Ga]Exendin-4, beta cell imaging, insulinoma, dosimetry
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-261629 (URN)978-91-554-9323-3 (ISBN)
Public defence
2015-10-23, Fåhraeussalen, Rudbecklaboratoriet (hus C5), Dag Hammarskjölds väg 20, 751 85, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-10-06 Created: 2015-09-02 Last updated: 2015-10-12

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Selvaraju, Ram KumarVelikyan, IrinaBerglund, MarieLubberink, MarkJohansson, LarsKorsgren, OlleEriksson, Olof

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Selvaraju, Ram KumarVelikyan, IrinaBerglund, MarieLubberink, MarkJohansson, LarsKorsgren, OlleEriksson, Olof
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Preclinical PET PlatformBiomedical Radiation SciencesSection of Nuclear Medicine and PETRadiologyClinical Immunology
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European Journal of Nuclear Medicine and Molecular Imaging
Radiology, Nuclear Medicine and Medical Imaging

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