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Velikyan, I.* ; Haack, T.* ; Bossart, M.* ; Evers, A.* ; Laitinen, I.* ; Larsen, P.* ; Plettenburg, O. ; Johansson, L.* ; Pierrou, S.* ; Wagner, M.* ; Eriksson, O.*

First-in-class positron emission tomography tracer for the glucagon receptor.

EJNMMI Res. 9:17 (2019)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.MethodsTwo 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 [Ga-68]Ga-DO3A-S01-GCG and [Ga-68]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[Ga-68]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. [Ga-68]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[Ga-68]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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Glucagon ; Gcg ; Glp-1 Receptor ; Dual Agonist ; Type 2 Diabetes; Peptide-1 Receptor; Spect
ISSN (print) / ISBN 2191-219X
e-ISSN 2191-219X
Zeitschrift EJNMMI Research
Quellenangaben Band: 9, Heft: , Seiten: , Artikelnummer: 17 Supplement: ,
Verlag Springer
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Medicinal Chemistry (IMC)