Naoya Kondo1, Ayaka Oishi1, Masahiko Hirata1, Takashi Temma2. 1. Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan. 2. Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan. ttemma@gly.oups.ac.jp.
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.
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.
Authors: Damian Wild; Martin Béhé; Andreas Wicki; Daniel Storch; Beatrice Waser; Martin Gotthardt; Boris Keil; Gerhard Christofori; Jean Claude Reubi; Helmut R Mäcke Journal: J Nucl Med Date: 2006-12 Impact factor: 10.057
Authors: Grazia Daniela Femminella; Eleni Frangou; Sharon B Love; Gail Busza; Clive Holmes; Craig Ritchie; Robert Lawrence; Brady McFarlane; George Tadros; Basil H Ridha; Carol Bannister; Zuzana Walker; Hilary Archer; Elizabeth Coulthard; Ben R Underwood; Aparna Prasanna; Paul Koranteng; Salman Karim; Kehinde Junaid; Bernadette McGuinness; Ramin Nilforooshan; Ajay Macharouthu; Andrew Donaldson; Simon Thacker; Gregor Russell; Naghma Malik; Vandana Mate; Lucy Knight; Sajeev Kshemendran; John Harrison; Christian Hölscher; David J Brooks; Anthony Peter Passmore; Clive Ballard; Paul Edison Journal: Trials Date: 2019-04-03 Impact factor: 2.279