Development of an ¹¹¹In-Labeled Glucagon-Like Peptide-1 Receptor-Targeting Exendin-4 Derivative that Exhibits Reduced Renal Uptake.

Insulinomas are neuroendocrine tumors that are mainly found in the pancreas. Surgical resection is currently the first-line treatment for insulinomas; thus, it is vital to preoperatively determine their locations. The marked expression of the glucagon-like peptide-1 receptor (GLP-1R) is seen in pancreatic β-cells and almost all insulinomas. Radiolabeled derivatives of exendin-4, a GLP-1R agonist, have been used with nuclear medicine imaging techniques for the detection of the GLP-1R; however, their marked renal accumulation can hinder the imaging of pancreatic tail lesions. To develop a GLP-1R imaging probe that exhibits reduced renal accumulation, we designed and synthesized a straight-chain GLP-1R-targeting radioligand, [In]In-E4DA1, which consisted of exendin-4, DOTADG (a chelator), and an (iodophenyl)butyric acid derivative (an albumin binder [ALB]). We performed preclinical evaluations of [In]In-E4DA1 to investigate its utility as a GLP-1R imaging probe. [In]In-E4DA1 and [In]In-E4D (a control compound lacking the ALB moiety) were prepared by reacting the corresponding precursors with [In]InCl in buffer. Cell-binding and human serum albumin (HSA)-binding assays were performed to assess the affinity of the molecules for INS-1 (GLP-1R-positive) cells and albumin, respectively. A biodistribution assay and single-photon emission computed tomography imaging were carried out using INS-1 tumor-bearing mice. In the cell-binding assay, [In]In-E4DA1 and [In]In-E4D exhibited binding to INS-1 cells. In the HSA-binding assay, [In]In-E4DA1 bound to HSA, while [In]In-E4D showed little HSA binding. The experiments involving INS-1 tumor-bearing mice revealed that the introduction of an ALB moiety into the DOTADG-based exendin-4 derivative markedly increased the molecule's tumor accumulation while decreasing its renal accumulation. In addition, [In]In-E4DA1 exhibited greater tumor accumulation than renal accumulation, whereas previously reported radiolabeled exendin-4 derivatives demonstrated much higher accumulation in the kidneys than in tumors. These results indicate that [In]In-E4DA1 may be a useful GLP-1R imaging probe, as it demonstrates only slight renal accumulation.