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First-in-class posi...
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Velikyan, Irina,1966-Uppsala universitet,Radiologi,Uppsala Univ Hosp, PET Ctr, Ctr Med Imaging, Uppsala, Sweden
(författare)
First-in-class positron emission tomography tracer for the glucagon receptor
- Artikel/kapitelEngelska2019
Förlag, utgivningsår, omfång ...
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2019-02-15
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Springer Science and Business Media LLC,2019
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electronicrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-378994
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-378994URI
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https://doi.org/10.1186/s13550-019-0482-0DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement.Methods: Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [68Ga]Ga-DO3A-S01-GCG and [68Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat.Results: [68Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals.Conclusion: [68Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Haack, TorstenSanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
(författare)
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Bossart, MartinSanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
(författare)
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Evers, AndreasSanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
(författare)
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Laitinen, IinaSanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
(författare)
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Larsen, PhilipSanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
(författare)
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Plettenburg, OliverGerman Res Ctr Environm Hlth GmbH, Inst Med Chem, Helmholtz Zentrum Munchen, Neuherberg, Germany; Leibniz Univ Hannover, Inst Organ Chem, Hannover, Germany
(författare)
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Johansson, LarsAntaros Med AB, Uppsala Sci Pk, Uppsala, Sweden
(författare)
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Pierrou, StefanAntaros Med AB, Uppsala Sci Pk, Uppsala, Sweden
(författare)
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Wagner, MichaelSanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
(författare)
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Eriksson, OlofUppsala universitet,Science for Life Laboratory, SciLifeLab,Antaros Med AB, Uppsala Sci Pk, Uppsala, Sweden(Swepub:uu)oloer586
(författare)
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Uppsala universitetRadiologi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:EJNMMI Research: Springer Science and Business Media LLC92191-219X
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Velikyan, Irina, ...
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Haack, Torsten
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Bossart, Martin
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Evers, Andreas
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Laitinen, Iina
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Larsen, Philip
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visa fler...
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Plettenburg, Oli ...
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Johansson, Lars
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Pierrou, Stefan
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Wagner, Michael
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Eriksson, Olof
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visa färre...
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Uppsala universitet