Development of in vivo imaging agents targeting glucagon-like peptide-1 receptor (GLP-1R) in pancreatic islets

Objectives The beta cell mass is known to decrease as diabetes progresses. Developing a method to measure beta cell mass in vivo would be useful for the early diagnosis of diabetes. High densities of GLP-1R expression in pancreatic islets provide an attractive target for imaging. In this study, based on the GLP-1R antagonist exendin-(9-39) [ex(9-39)], we developed in vivo imaging agents specifically targeting GLP-1R.

Methods N-succinimidyl 4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) labeled [ex(9-39)] derivatives were synthesized and evaluated. To evaluate the distribution of [¹⁸F]FB-[ex(9-39)] derivatives in vivo, a biodistribution study was carried out in normal and GLP-1R KO mice. PET imaging studies were performed.

Results The decay-corrected radiochemical yield of [¹⁸F]FB-[ex(9-39)] derivatives was about 7~18% and the radiochemical purity was greater than 99%. In vitro binding study indicated that the affinity of cold FB-[ex(9-39)] derivatives to GLP-1R was similar to ex(9-39). The in vivo biodistribution of [¹⁸F]FB12 and [¹⁸F]FB27-[ex(9-39)] in mice showed the high uptake in the pancreas (4.7% ID/g at 30 min and 4.1% ID/g at 15 min postinjection, respectively). A significant reduction of pancreas uptake was confirmed in GLP-IR KO mice. Moreover, we succeeded in visualizing the pancreas by PET.

Conclusions For non-invasive imaging of pancreatic beta cells, ex(9-39) and GLP-1R can serve as a useful probe and target molecule, respectively.