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Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Antaros Med AB, Molndal, Sweden.ORCID iD: 0000-0002-2515-8790
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Sanofi Aventis, Frankfurt, Germany.
Sanofi Aventis, Frankfurt, Germany.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 14960Article in journal (Refereed) Published
Abstract [en]

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 [Ga-68]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. [Ga-68]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 mu g/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [Ga-68]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [Ga-68]GaDO3A-S01-GCG binding in liver. [Ga-68]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 mu g/kg. In vivo K-d for [Ga-68]Ga-DO3A-S01-GCG corresponded to 0.7 mu g/kg, which indicates high potency. The test-retest reproducibility for [Ga-68]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 [Ga-68]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [Ga-68]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 9, article id 14960
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Radiology, Nuclear Medicine and Medical Imaging
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URN: urn:nbn:se:uu:diva-399094DOI: 10.1038/s41598-019-51530-0ISI: 000490988200019PubMedID: 31628379OAI: oai:DiVA.org:uu-399094DiVA, id: diva2:1379048
Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2019-12-16Bibliographically approved

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