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The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2018 (English)In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 8, article id 113Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand.

METHODS: The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments.

RESULTS: The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy.

CONCLUSION: We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.

Place, publisher, year, edition, pages
2018. Vol. 8, article id 113
Keywords [en]
Beta cell imaging, Beta cell mass, Diabetes, G-protein-coupled receptor 44 (GPR44), Islet imaging
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-373205DOI: 10.1186/s13550-018-0465-6ISI: 000454413500002PubMedID: 30588560OAI: oai:DiVA.org:uu-373205DiVA, id: diva2:1277799
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Diabetes AssociationNovo NordiskSwedish Child Diabetes FoundationEXODIAB - Excellence of Diabetes Research in SwedenAvailable from: 2019-01-11 Created: 2019-01-11 Last updated: 2019-01-16Bibliographically approved

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Selvaraju, RamkumarKorsgren, OlleEriksson, Olof

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