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

Targeting of the Glucose-dependent Insulinotropic Polypeptide receptor GIPR is an emerging strategy in anti-diabetic 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 Gallium-68. 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, was assessed in non-human primates (NHP) by PET.

[⁶⁸Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo pancreatic binding in NHP could be dose dependently inhibited by co-injection of unlabelled S02-GIP-T4. Finally, subcutaneous pre-treatment 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, non-invasive, and quantitative assessment of GIPR target distribution and drug occupancy.