Journal
MOLECULAR PHARMACEUTICS
Volume 19, Issue 3, Pages 1019-1027Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.2c00068
Keywords
GLP-1R; insulinoma; exendin-4; In-111; albumin binder
Funding
- AMED [JP20im0210819]
- Nihon Medi-Physics Co., Ltd.
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A GLP-1R imaging probe [In-111]In-E4DA1 has been developed, which can detect the location of insulinomas in vivo and has reduced renal accumulation.
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 glucagonlike peptide-1 receptor (GLP-1R) is seen in pancreatic beta-cells and almost all insulinomas. Radiolabeled derivatives of exendin-4, a GLP-1R agonist, have been used with nuclear medicine imaging techniques for the in vivo 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-111]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-111]In-E4DA1 to investigate its utility as a GLP-1R imaging probe. [In-111]In-E4DA1 and [In-111]In-E4D (a control compound lacking the ALB moiety) were prepared by reacting the corresponding precursors with [In-111]InCl3 in buffer. Cell-binding and human serum albumin (HSA)-binding assays were performed to assess the in vitro 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-111]In-E4DA1 and [In-111]In-E4D exhibited in vitro binding to INS-1 cells. In the HSAbinding assay, [In-111]In-E4DA1 bound to HSA, while [In-111]In-E4D showed little HSA binding. The in vivo 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-111]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-111]In-E4DA1 may be a useful GLP-1R imaging probe, as it demonstrates only slight renal accumulation.
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