Evaluation of newly synthesized ⁶⁸Ga-labeled Exendin-4 derivative targeting glucagon-like peptide-1 receptor

Objectives Insulinoma is a tumor derived from a pancreatic β-cell, and it is a disease with the hypoglycemia due to the hyperinsulinoma. Recent studies have reported frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas. So, a radiolabeled compound bound to GLP-1R has been expected to be useful for imaging insulinoma. In addition, GLP-1R is a promising molecule for pancreatic β-cell imaging. Exendin-4 is the natural peptide mimetic of GLP-1. In this study, we synthesized ⁶⁸Ga-labeled Exendin-4 ([⁶⁸Ga]Df12-Ex4) targeting GLP-1R, and evaluated its utility as a probe for PET imaging of insulinoma.

Methods The binding affinity of Ga-Df12-Ex4 to human GLP-1R was evaluated by competitive binding assay using the prepared membranes. Biodistribution studies were carried out in INS-1 xenografted mice. PET imaging was carried out in INS-1 xenografted mice. In addition, stability of [⁶⁸Ga]Df12-Ex4 in vivo was evaluated by analysis of the extracted tumor homogenate with reverse phase HPLC analysis.

Results Ga-Df12-Ex4 had high affinity for GLP-1R (IC₅₀ = 17 nM). The in vivo biodistribution of [⁶⁷Ga]Df12-Ex4 in INS-1 xenografted mice showed a high uptake in the tumor (30 %ID/g at 1 hr) and high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B = 9.8, T/M = 51, T/P = 1.8 at 1 hr). Preadministration of excess nonradioactive exendin(9-39) significantly reduced accumulation in the tumor and the pancreas (83% and 94% inhibition, respectively) at 1hr after [⁶⁷Ga]Df12-Ex4 injection, indicating that major fractions of the uptakes of [⁶⁷Ga]Df12-Ex4 in the tumor and pancreas were mediated by the GLP-1R. PET studies with [⁶⁸Ga]Df12-Ex4 in mice showed the clear image of the tumor 30 min after injection. In addition, [⁶⁸Ga]Df12-Ex4 showed high stability in vivo.

Conclusions We demonstrated that a newly synthesized [⁶⁸Ga]Df12-Ex4 has a potential as imaging probe targeting for insulionma.