Development of 111In-labeled Exendin(9-39) Derivatives for Single-Photon Emission Computed Tomography Imaging of Insulinoma

Publication date: Available online 3 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Hiroyuki Kimura, Hirokazu Matsuda, Yu Ogawa, Hiroyuki Fujimoto, Kentaro Toyoda, Naotaka Fujita, Kenji Arimitsu, Keita Hamamatsu, Yusuke Yagi, Masahiro Ono, Nobuya Inagaki, Hideo Saji
Insulinoma is a tumor derived from pancreatic β-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia. In this study, we synthesized a novel indium-111 (¹¹¹In)-benzyl-diethylenetriaminepentaacetic acid (¹¹¹In-BnDTPA)-conjugated exendin(9-39), ¹¹¹In-BnDTPA-exendin(9-39), and evaluated its utility as a probe for the SPECT imaging of insulinoma. ^natIn-BnDTPA-exendin(9-39) exhibited a high affinity for GLP-1R (IC50 = 2.5 nM), stability in plasma, and a specific activity that improved following reactions with a solvent and solubilizer. Regarding the in vivo biodistribution of ¹¹¹In-BnDTPA-exendin(9-39) in INS-1 tumor-bearing mice, high uptake levels were observed in tumors (14.6% ID/g at 15 min), with corresponding high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B = 2.55, T/M = 22.7, T/P = 2.7 at 1 h). The pre-administration of excess nonradioactive exendin(9-39) significantly reduced accumulation in both the tumor and pancreas (76% and 68% inhibition, respectively) at 1 h after ¹¹¹In-BnDTPA-exendin(9-39) injection, indicating that the GLP-1R mediated a majority of ¹¹¹In-BnDTPA-exendin(9-39) uptake in the tumor and pancreas. Finally, ¹¹¹In-BnDTPA-exendin(9-39) SPECT/CT studies in mice yielded clear images of tumors at 30 min post-injection. These results suggest that ¹¹¹In-BnDTPA-exendin(9-39) could be a useful SPECT molecular imaging probe for the detection and exact localization of insulinomas.

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