First-in-class positron emission tomography tracer for the glucagon receptor View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-12

AUTHORS

Irina Velikyan, Torsten Haack, Martin Bossart, Andreas Evers, Iina Laitinen, Philip Larsen, Oliver Plettenburg, Lars Johansson, Stefan Pierrou, Michael Wagner, Olof Eriksson

ABSTRACT

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. More... »

PAGES

17

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13550-019-0482-0

DOI

http://dx.doi.org/10.1186/s13550-019-0482-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112168851

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30771019


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