Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2-piperidin-1-yl-phenyl) -butyl-carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic β-cell mass with positron emission tomography (PET)

18F-labeled non-sulfonylurea hypoglycemic agent (S)-2-(2-[18F]fluoroethoxy)-4-((3-methyl-1-(2-piperidin-1-yl-phenyl) -butylcarbamoyl)-methyl)-benzoic acid ([18F]repaglinide), a derivative of the sulfonylurea-receptor (SUR) ligand repaglinide, was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. [18F]Repaglinide could be obtained in an overall radiochemical yield (RCY) of 20% after 135 min with a radiochemical purity higher than 98% applying the secondary labeling precursor 2-[18F]fluoroethyltosylate. Specific activity was in the range of 50-60 GBq/μmol. Labeling was conducted by exchanging the ethoxy-moiety into a 2-[18F]fluoroethoxy group. To characterize the properties of fluorinated repaglinide, the affinity of the analogous non-radioactive 19F-compound for binding to the human SUR1 isoform was assessed. [19F]Repaglinide induced a complete monophasic inhibition curve with a Hill coefficient close to 1 (1.03) yielding a dissociation constant (KD) of 134 nM. Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide. Finally, biodistribution of [18F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection. Pancreatic tissue displayed a stable accumulation of ∼0.12% of the injected dose from 10 min to 30 min p.i.. 50% of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide, indicating that [18F]repaglinide might be suitable for in vivo investigation with PET