Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates

authored by

Olof Eriksson, Irina Velikyan, Torsten Haack, Martin Bossart, Andreas Evers, Iina Laitinen, Philip J. Larsen, Oliver Plettenburg, Akihiro Takano, Christer Halldin, Gunnar Antoni, Lars Johansson, Stefan Pierrou, Michael Wagner

Abstract

The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [⁶⁸Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [⁶⁸Ga]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 µg/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [⁶⁸Ga]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [⁶⁸Ga]Ga-DO3A-S01-GCG binding in liver. [⁶⁸Ga]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2 µg/kg. In vivo K_d for [⁶⁸Ga]Ga-DO3A-S01-GCG corresponded to 0.7 µg/kg, which indicates high potency. The test-retest reproducibility for [⁶⁸Ga]Ga-DO3A-S01-GCG binding in liver was 5.7 ± 7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5 ± 9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [⁶⁸Ga]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [⁶⁸Ga]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.

Organisation(s)

Institute of Organic Chemistry

External Organisation(s)

Uppsala University
Sanofi-Aventis Deutschland GmbH
Bayer AG
Helmholtz Zentrum München - German Research Center for Environmental Health
Nanyang Technological University (NTU)
Antaros Medical AB
Karolinska Institutet

Type

Article

Journal

Scientific reports

Volume

9

ISSN

2045-2322

Publication date

18.10.2019

Publication status

E-pub ahead of print

Peer reviewed

Yes

ASJC Scopus subject areas

General

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1038/s41598-019-51530-0 (Access: Open)