Indirectly radioiodinated exendin-4 as an analytical tool for in vivo detection of glucagon-like peptide-1 receptor in a
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ORIGINAL ARTICLE
Indirectly radioiodinated exendin‑4 as an analytical tool for in vivo detection of glucagon‑like peptide‑1 receptor in a disease setting Naoya Kondo1 · Ayaka Oishi1 · Masahiko Hirata1 · Takashi Temma1 Received: 6 August 2020 / Accepted: 7 October 2020 © The Japanese Society of Nuclear Medicine 2020
Abstract Objective Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been reported to have therapeutic effects on diabetes and various diseases. Precise detection of GLP-1 receptor (GLP-1R) can be useful to diagnose and elucidate the mechanism of such diseases. Here we aimed to develop an imaging probe based on GLP-1RA that has high molar activity and sensitivity for detection of low-level GLP-1R expression in non-pancreatic diseases. Methods We selected the agonist exenatide (Ex4) as the parent peptide of a GLP-1R targeting probe and prepared Cys-Ex4 by addition of an N-terminal Cys residue and labeling with the prosthetic agent N-(3-[125I]iodophenyl)maleimide ([125I]IPM) to generate [125I]Ex4ipm. We evaluated the affinity of [125I]Ex4ipm for GLP-1R, as well as cellular binding profiles in insulinoma and prostate cancer cell lines, and in vivo biodistributions in normal and tumor-bearing mice to assess GLP-1R-dependent accumulation of radioactivity in tissues. Results [125I]Ex4ipm was easily synthesized with high radiochemical yield (73%), radiochemical purity (> 99%), and molar activity (81 GBq/µmol) via a thiol/maleimide reaction. Following administration to mice, [ 125I]Ex4ipm accumulated to high levels in the pancreas (23.3% ID/g), with radioactivity co-localizing in areas having insulin-positive β cells. High amounts of radioactivity also accumulated in insulinomas that overexpressed GLP-1R (27.5% ID/g). In contrast, low amounts of [125I]Ex4ipm accumulation, corresponding to low expression levels of GLP-1R, were observed in prostate cancer cells and xenografts used as a model of non-pancreatic applications. Conclusion Our results suggested that [ 123I]Ex4ipm could be valuable for GLP-1R imaging in diabetes, insulinomas, and various diseases related to GLP-1R. Keywords Molecular imaging · Glucagon-like peptide-1 receptor · Exendin-4 · Radioiodine
Introduction The ligand for glucagon-like peptide-1 receptor (GLP-1R) is the biological hormone GLP-1 [1]. GLP-1R expressed in pancreatic β cells is involved in regulation of insulin release, and is an effective therapeutic target for diabetes [2, 3], as evidenced by the successful use of GLP-1R agonists (GLP1RA) and DPP4 inhibitors to treat diabetes [4, 5]. In nuclear medical imaging, visualization of GLP-1R expression is an effective method for quantification of pancreatic β cell mass [6], monitoring islet mass and function after transplantation * Takashi Temma [email protected] 1
Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4‑20‑1 Nasahara, Takatsuki, Osaka 569‑1094, Japan
[7, 8], and defining localization of insulinomas [9]. A variety of radiolabeled derivatives of the GLP-1R agonist (GLP
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