Evaluation of 18F-labeled exendin(9-39) derivatives targeting glucagon-like peptide-1 receptor for pancreatic β-cell imaging

Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 2
Author(s): Hiroyuki Kimura, Yu Ogawa, Hiroyuki Fujimoto, Eri Mukai, Hidekazu Kawashima, Kenji Arimitsu, Kentaro Toyoda, Naotaka Fujita, Yusuke Yagi, Keita Hamamatsu, Takaaki Murakami, Atsushi Murakami, Masahiro Ono, Yuji Nakamoto, Kaori Togashi, Nobuya Inagaki, Hideo Saji
β-cell mass (BCM) is known to be decreased in subjects with type-2 diabetes (T2D). Quantitative analysis for BCM would be useful for understanding how T2D progresses and how BCM affects treatment efficacy and for earlier diagnosis of T2D and development of new therapeutic strategies. However, a noninvasive method to measure BCM has not yet been developed.We developed four ¹⁸F-labeled exendin(9-39) derivatives for β-cell imaging by PET: [¹⁸F]FB9-Ex(9-39), [¹⁸F]FB12-Ex(9-39), [¹⁸F]FB27-Ex(9-39), and [¹⁸F]FB40-Ex(9-39). Affinity to the glucagon-like peptide-1 receptor (GLP-1R) was evaluated with dispersed islet cells of ddY mice. Uptake of exendin(9-39) derivatives in the pancreas as well as in other organs was evaluated by a biodistribution study. Small-animal PET study was performed after injecting [¹⁸F]FB40-Ex(9-39).FB40-Ex(9-39) showed moderate affinity to the GLP-1R. Among all of the derivatives, [¹⁸F]FB40-Ex(9-39) resulted in the highest uptake of radioactivity in the pancreas 30 min after injection. Moreover, it showed significantly less radioactivity accumulated in the liver and kidney, resulting in an overall increase in the pancreas-to-organ ratio. In the PET imaging study, pancreas was visualized at 30 min after injection of [¹⁸F]FB40-Ex(9-39).[¹⁸F]FB40-Ex(9-39) met the basic requirements for an imaging probe for GLP-1R in pancreatic β-cells. Further enhancement of pancreatic uptake and specific binding to GLP-1R will lead to a clear visualization of pancreatic β-cells.

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