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First-in-class posi...
First-in-class positron emission tomography tracer for the glucagon receptor
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- Velikyan, Irina, 1966- (author)
- Uppsala universitet,Radiologi,Uppsala Univ Hosp, PET Ctr, Ctr Med Imaging, Uppsala, Sweden
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- Haack, Torsten (author)
- Sanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
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- Bossart, Martin (author)
- Sanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
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- Evers, Andreas (author)
- Sanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
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- Laitinen, Iina (author)
- Sanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
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- Larsen, Philip (author)
- Sanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
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- Plettenburg, Oliver (author)
- German Res Ctr Environm Hlth GmbH, Inst Med Chem, Helmholtz Zentrum Munchen, Neuherberg, Germany; Leibniz Univ Hannover, Inst Organ Chem, Hannover, Germany
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- Johansson, Lars (author)
- Antaros Med AB, Uppsala Sci Pk, Uppsala, Sweden
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- Pierrou, Stefan (author)
- Antaros Med AB, Uppsala Sci Pk, Uppsala, Sweden
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- Wagner, Michael (author)
- Sanofi Aventis Deutschland GmbH, Ind Pk Hochst, Frankfurt, Germany
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- Eriksson, Olof (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Antaros Med AB, Uppsala Sci Pk, Uppsala, Sweden
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(creator_code:org_t)
- 2019-02-15
- 2019
- English.
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In: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 9
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Abstract
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Keyword
- Glucagon
- GCG
- GLP-1 receptor
- Dual agonist
- Type 2 diabetes
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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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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show more...
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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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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Radiology Nuclea ...
- Articles in the publication
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EJNMMI Research
- By the university
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Uppsala University