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|Title:||The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass||Authors:||Jahan, Mahabuba
Selvaraju, Ram K.
Winzell, Maria Sörhede
Beta Cell Imaging
G-Protein-Coupled Receptor 44 (GPR44)
|Issue Date:||2018||Source:||Jahan, M., Johnström, P., Selvaraju, R. K., Svedberg, M., Winzell, M. S., Bernström, J., . . . Eriksson, O. (2018). The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass. EJNMMI Research, 8, 113-. doi:10.1186/s13550-018-0465-6||Series/Report no.:||EJNMMI Research||Abstract:||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.||URI:||https://hdl.handle.net/10356/103580
|DOI:||http://dx.doi.org/10.1186/s13550-018-0465-6||Rights:||© 2018 The Author(s). Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made.||metadata.item.grantfulltext:||open||metadata.item.fulltext:||With Fulltext|
|Appears in Collections:||LKCMedicine Journal Articles|
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