Synthesis and evaluation of radioiodinated exendin derivatives for the imaging of GLP-1 receptor expression in pancreatic islets

Objectives The β-cell mass is known to decrease as diabetes progresses. Thus, measuring changes in β-cell mass in vivo is important not only for understanding the pathogenesis but also for facilitating early diagnosis and developing improved treatments for type 1 and 2 diabetes. High densities of GLP-1 receptor (GLP-1R) expression in pancreatic islets provide an attractive target for imaging. In this study, based on the GLP-1R antagonist exendin, we developed a SPECT tracer specifically targeting GLP-1R.

Methods [^123/125I] labeled exendin derivatives were synthesized and evaluated. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Biodistribution was carried out in normal mice. Ex vivo autoradiography was carried out in transgenic mice expressing green fluorescent protein (GFP) under control of the mouse insulin I gene promoter (MIP) (MIP-GFP mice).

Results In vitro binding study indicated that the affinity of exendin derivatives to GLP-1R was similar to natural exendin. The in vivo biodistribution of [¹²⁵I]KUEx-1,2 and 3 in mice showed the high uptake in the pancreas (29% ID/g at 120min, 45% ID/g at 30min and 13% ID/g at 15min postinjection, respectively).The high pancreas-to-liver (P/L) ratio may be important because of its proximity to the pancreas. At 30min after injection of [¹²⁵I]KUEx-2, a significantly higher P/L ratio was obtained (P/L = 6.8). Ex vivo autoradiography showed that the intensity of the fluorescent signals of the pancreatic sections of MIP-GFP mice also correlated with that of the radioactive signals, indicating specific high binding of [¹²⁵I]KUEx-2 in pancreatic β-cells.

Conclusions These data suggest that [^123/125I]KUEx-2 can be a potential candidate as a SPECT tracer for measuring β-cell mass in pancreatic islets