The development of a GPR44 targeting radioligand [(11)C]AZ12204657 for in vivo assessment of beta cell mass

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 (11)C- or (3)H-labeled methyl iodide ([(11)C/(3)H]CH(3)I) in one step, and the conversion of [(11)C/(3)H]CH(3)I to the radiolabeled product [(11)C/(3)H]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 [(11)C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [(3)H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [(11)C/(3)H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [(11)C]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 [(11)C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [(3)H]AZ12204657 and [(11)C]AZ12204657 selectively target pancreatic beta cells. [(11)C]AZ12204657 has promising properties as a marker for human BCM.