Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography

authored by: Olof Eriksson, Irina Velikyan, Torsten Haack, Martin Bossart, Andreas Evers, Katrin Lorenz, Iina Laitinen, Philip J. Larsen, Oliver Plettenburg, Lars Johansson, Stefan Pierrou, Michael Wagner
Abstract: Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with 68Ga. The resulting PET tracer [68Ga]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [68Ga]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [68Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [68Ga]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [68Ga]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [68Ga]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
External Organisation(s): Uppsala University
Sanofi-Aventis Deutschland GmbH
Bayer AG
Helmholtz Zentrum München - German Research Center for Environmental Health
Antaros Medical AB
Type: Article
Journal: DIABETES
Volume: 70
Pages: 842-853
No. of pages: 12
ISSN: 0012-1797
Publication date: 19.04.2021
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: Internal Medicine, Endocrinology, Diabetes and Metabolism
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Electronic version(s): https://doi.org/10.2337/db20-1096 (Access: Open)