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Assessment of gluca...
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Eriksson, OlofUppsala universitet,Institutionen för läkemedelskemi,Science for Life Laboratory, SciLifeLab,Antaros Med AB, Molndal, Sweden
(author)
Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates
- Article/chapterEnglish2019
Publisher, publication year, extent ...
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2019-10-18
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Springer Science and Business Media LLC,2019
Numbers
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LIBRIS-ID:oai:prod.swepub.kib.ki.se:142120011
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http://kipublications.ki.se/Default.aspx?queryparsed=id:142120011URI
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https://doi.org/10.1038/s41598-019-51530-0DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-399094URI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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.
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Velikyan, Irina,1966-Uppsala universitet,Institutionen för läkemedelskemi(Swepub:uu)irinveli
(author)
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Haack, TSanofi Aventis, Frankfurt, Germany
(author)
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Bossart, MSanofi Aventis, Frankfurt, Germany
(author)
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Evers, ASanofi Aventis, Frankfurt, Germany
(author)
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Laitinen, ISanofi Aventis, Frankfurt, Germany
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Larsen, PJSanofi Aventis, Frankfurt, Germany;Bayer Pharmaceut, Wuppertal, Germany
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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)
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Takano, AKarolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Cty Council, Stockholm, Sweden
(author)
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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)
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Antoni, GunnarUppsala universitet,Institutionen för läkemedelskemi(Swepub:uu)gunnarat
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Johansson, LAntaros Med AB, Molndal, Sweden
(author)
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Pierrou, SAntaros Med AB, Molndal, Sweden
(author)
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Wagner, MSanofi Aventis, Frankfurt, Germany
(author)
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Uppsala universitetInstitutionen för läkemedelskemi
(creator_code:org_t)
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In:Scientific reports: Springer Science and Business Media LLC9:1, s. 14960-2045-2322
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Eriksson, Olof
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Velikyan, Irina, ...
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Haack, T
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Bossart, M
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Evers, A
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Laitinen, I
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Larsen, PJ
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Plettenburg, O
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Takano, A
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Halldin, C
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Antoni, Gunnar
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Johansson, L
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Pierrou, S
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Wagner, M
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