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

verfasst von

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.

Externe Organisation(en)

Uppsala University
Sanofi-Aventis Deutschland GmbH
Bayer AG
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Antaros Medical AB

Typ

Artikel

Journal

DIABETES

Band

70

Seiten

842-853

Anzahl der Seiten

12

ISSN

0012-1797

Publikationsdatum

19.04.2021

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Innere Medizin, Endokrinologie, Diabetes und Stoffwechsel

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.2337/db20-1096 (Zugang: Offen)