Development of ¹¹¹In-labeled Exendin-4 derivative for the imaging of glucagon-like peptide-1 receptor expression in pancreatic islets

Objectives The pancreatic β-cell mass is known to decrease as diabetes progresses. Thus, if a decrease in the amount of pancreatic β-cells can be detected at an early stage, there is a possibility of the prevention and treatment for diabetes. High densities of glucagon-like peptide-1 receptor (GLP-1R) expression in pancreatic β-cells provide an attractive target for imaging. Exendin-4 (Ex4), a peptide analog of GLP-1, can bind with high affinity to GLP-1R and is more stable than GLP-1 in vivo. In this study, we developed ¹¹¹In-labeled Exendin-4 (¹¹¹In-DTPA12-Ex4) targeting GLP-1R, and evaluated its utility as a SPECT probe for imaging of pancreatic GLP-1R.

Methods The binding affinity of In-DTPA12-Ex4 to human GLP-1R was evaluated by competitive binding assay using the prepared membranes. The in vitro stability was characterized in mouse plasma. Biodistribution studies were carried out in normal ddY mice and STZ-treated diabetic mice. SPECT imaging was performed after injection of ¹¹¹In-DTPA12-Ex4 into ddY mice.

Results In-DTPA12-Ex4 had high affinity for GLP-1R (IC50 = 0.43 nM). ¹¹¹In-DTPA12-Ex4 was stable in mouse plasma for 4 h. The in vivo biodistribution of ¹¹¹In-DTPA12-Ex4 in ddy mice showed a high uptake in the pancreas (21.0 %ID/g at 1 hr) and high pancreas-to-blood (P/B = 41.7) and pancreas-to-liver (P/L = 14) ratios. The pancreas uptake of ¹¹¹In-DTPA12-Ex4 in STZ-treated diabetic mice was decreased depending on fasting blood glucose level. Moreover, in SPECT images, pancreas was visualized by animal SPECT.

Conclusions We demonstrated that ¹¹¹In-DTPA12-Ex4 has a potential as an imaging probe detecting pancreatic GLP-1R.