We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography.
- Authors
Eriksson, Olof; Velikyan, Irina; Haack, Torsten; Bossart, Martin; Evers, Andreas; Lorenz, Katrin; Laitinen, Iina; Larsen, Philip J.; Plettenburg, Oliver; Johansson, Lars; Pierrou, Stefan; Wagner, Michael
- 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.
- Subjects
POSITRON emission tomography; DRUG development; GLUCOSE metabolism; PHYSICAL &; theoretical chemistry; RESEARCH; ANIMAL experimentation; RESEARCH methodology; CELL receptors; HYPOGLYCEMIC agents; MEDICAL cooperation; EVALUATION research; CELLULAR signal transduction; RATS; COMPARATIVE studies
- Publication
Diabetes, 2021, Vol 70, Issue 4, p842
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db20-1096