First-in-class positron emission tomography tracer for the glucagon receptor

authored by

Irina Velikyan, Torsten Haack, Martin Bossart, Andreas Evers, Iina Laitinen, Philip Larsen, Oliver Plettenburg, Lars Johansson, Stefan Pierrou, Michael Wagner, Olof Eriksson

Abstract

Abstract: The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement. Methods: Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [ ⁶⁸ Ga]Ga-DO3A-S01-GCG and [ ⁶⁸ Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat. Results: [ ⁶⁸ Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [ ⁶⁸ Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals. Conclusion: [ ⁶⁸ Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans.

Organisation(s)

Institute of Organic Chemistry

External Organisation(s)

Uppsala University
Sanofi-Aventis Deutschland GmbH
Helmholtz Zentrum München - German Research Center for Environmental Health
Antaros Medical AB

Type

Article

Journal

EJNMMI Research

Volume

9

ISSN

2191-219X

Publication date

15.02.2019

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Radiology Nuclear Medicine and imaging

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1186/s13550-019-0482-0 (Access: Open)