68Ga-labelled-exendin-4: New GLP1R targeting agents for imaging pancreatic β-cell and insulinoma

Objective: Glucagon-like peptide-1 receptor (GLP1R) specifically expressed on the surface of pancreatic beta-cells and insulinoma, is a potential biomarker for imaging beta-cell mass (BCM). In this study, two new Ga-68-labelled GLP1R targeting agents were prepared and their biological properties for imaging BCM and insulinoma were evaluated. Methods: [Ga-68]Ga-HBED-CC-MAL-Cys(39)-exendin-4 ([Ga-68]Ga-4) and its dimer ([Ga-68]Ga-5) were synthesized from corresponding precursors. Cell uptake studies were evaluated in INS-1 cells. Biodistribution and microPET studies were performed in male normal Sprague-Dawley rats, diabetic rats and insulinoma xenograft NOD/SCID mice. Results: [Ga-68]Ga-4 and [Ga-68]Ga-5 were efficiently radiolabelled by a simple one-step reaction without purification leading to high radiochemical yields and radiochemical purities (both >95%, decay corrected, n = 6, molar activity 15 GBq/pmol). They both showed excellent stability (-95%) in phosphate-buffered saline, pH 7.4, and in rat serum (similar to 90%) for 2 h. Biodistribution studies and small animal PET/CT imaging showed that [Ga-68]Ga-4 displayed specific uptake in rat pancreas and mouse insulinoma, and a reduced uptake in the pancreas of diabetic rat was observed (similar to 62% reduction). Notably, it exhibited a rapid time-to-peak pancreatic uptake (0.96 +/- 0.19%ID/g in 15 min) and fast clearance from the kidney (42% clearance in 30 min). Results suggested a favorable in vivo kinetics for human imaging studies. Conclusions: [Ga-68]Ga-4 targeting GLP1R of pancreatic beta-cells may be a potentially useful PET agent and a suitable candidate for further structural modification studies. This agent has demonstrated several advantages, rapid time-to-peak pancreatic uptake and faster clearance from the kidney, factors may enhance diagnosis of diabetes and insulinoma. (C) 2021 Elsevier Inc. All rights reserved.