Abstract
BackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionWe 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.
Highlights
No validated biomarkers for assessment of beta cell mass (BCM) exist
The G-protein-coupled receptor 44 (GPR44), designated as the prostaglandin D2 (PGD2) receptor 2, DP2, or CRTh2, was recently identified in the pancreas as beta cell restricted in a proteomics screening effort [2]
The radiochemical purity was 98 ± 0.9% (n = 20) at end of the synthesis (EOS) and the identity of the radioligand was confirmed by co-injection of the radioligand with an authentic standard of AZ12204657 by radio-high-performance liquid chromatography (HPLC)
Summary
Accurate longitudinal imaging biomarkers reflecting pancreatic BCM are anticipated to foster progress in development of therapies, for type 1 and type 2 diabetes (T1D/ T2D) by for the first time enabling change in BCM as a clinical endpoint. This is of paramount importance for assessments of. The G-protein-coupled receptor 44 (GPR44), designated as the prostaglandin D2 (PGD2) receptor 2, DP2, or CRTh2, was recently identified in the pancreas as beta cell restricted in a proteomics screening effort [2]. 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
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