The development of a GPR44 targeting radioligand [11C]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.