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In Vivo Imaging of the Glucagonlike Peptide 1 Receptor in the Pancreas with Ga-68-Labeled DO3A-Exendin-4
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, Section of Nuclear Medicine and PET.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
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2013 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 8, 1458-1463 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2013. Vol. 54, no 8, 1458-1463 p.
Keyword [en]
beta-cell imaging, beta-cell mass, GLP-1R
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-206991DOI: 10.2967/jnumed.112.114066ISI: 000322692400061OAI: oai:DiVA.org:uu-206991DiVA: diva2:646424
Available from: 2013-09-09 Created: 2013-09-09 Last updated: 2017-12-06Bibliographically 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)
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Available from: 2015-10-06 Created: 2015-09-02 Last updated: 2015-10-12

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Selvaraju, Ram K.Velikyan, IrinaJohansson, LarsKorsgren, OlleEriksson, Olof

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