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

• Published in: Scientific reports Vol. 9; no. 1; p. 14960
• Main Authors: Eriksson, Olof, Velikyan, Irina, Haack, Torsten, Bossart, Martin, Evers, Andreas, Laitinen, Iina, Larsen, Philip J., Plettenburg, Oliver, Takano, Akihiro, Halldin, Christer, Antoni, Gunnar, Johansson, Lars, Pierrou, Stefan, Wagner, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.10.2019; Nature Publishing Group
• Subjects: 59/78; 631/154/53/2423; 692/53/2423; Agonists; Animals; Biomarkers; Biomarkers - metabolism; Diabetes mellitus; Dosimetry; Female; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - metabolism; Humanities and Social Sciences; Humans; Ligands; Liver; Liver - diagnostic imaging; Liver - metabolism; Macaca fascicularis; Male; Medicin och hälsovetenskap; multidisciplinary; Peptides; Peptides - metabolism; Positron emission tomography; Positron Emission Tomography Computed Tomography; Protein Binding; Radiation dosimetry; Radiometry; Rats; Rats, Sprague-Dawley; Receptors, Glucagon - metabolism; Reproducibility of Results; Science; Science (multidisciplinary); Spleen - diagnostic imaging
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51530-0

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 [ 68 Ga]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. [ 68 Ga]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 [ 68 Ga]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [ 68 Ga]Ga-DO3A-S01-GCG binding in liver. [ 68 Ga]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 [ 68 Ga]Ga-DO3A-S01-GCG corresponded to 0.7 µg/kg, which indicates high potency. The test-retest reproducibility for [ 68 Ga]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 [ 68 Ga]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [ 68 Ga]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.