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

Eriksson, OlofUppsala universitet,Institutionen för läkemedelskemi,Science for Life Laboratory, SciLifeLab,Antaros Med AB, Molndal, Sweden (author)

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 Kd 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.

Velikyan, Irina,1966-Uppsala universitet,Institutionen för läkemedelskemi(Swepub:uu)irinveli (author)
Haack, TSanofi Aventis, Frankfurt, Germany (author)
Bossart, MSanofi Aventis, Frankfurt, Germany (author)
Evers, ASanofi Aventis, Frankfurt, Germany (author)
Laitinen, ISanofi Aventis, Frankfurt, Germany (author)
Larsen, PJSanofi Aventis, Frankfurt, Germany;Bayer Pharmaceut, Wuppertal, Germany (author)
Plettenburg, OSanofi Aventis, Frankfurt, Germany;German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Med Chem, Neuherberg, Germany;Leibniz Univ Hannover, Inst Organ Chem, Hannover, Germany (author)
Takano, AKarolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Cty Council, Stockholm, Sweden (author)
Halldin, CKarolinska Institutet,Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Cty Council, Stockholm, Sweden;Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore (author)
Antoni, GunnarUppsala universitet,Institutionen för läkemedelskemi(Swepub:uu)gunnarat (author)
Johansson, LAntaros Med AB, Molndal, Sweden (author)
Pierrou, SAntaros Med AB, Molndal, Sweden (author)
Wagner, MSanofi Aventis, Frankfurt, Germany (author)
Uppsala universitetInstitutionen för läkemedelskemi (creator_code:org_t)

In:Scientific reports: Springer Science and Business Media LLC9:1, s. 14960-2045-2322

By the author/editor: Eriksson, Olof; Velikyan, Irina, ...; Haack, T; Bossart, M; Evers, A; Laitinen, I; show more...; Larsen, PJ; Plettenburg, O; Takano, A; Halldin, C; Antoni, Gunnar; Johansson, L; Pierrou, S; Wagner, M; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Radiology Nuclea ...

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