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First-in-class positron emission tomography tracer for the glucagon receptor.
EJNMMI Res. 9:17 (2019)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Glucagon ; Gcg ; Glp-1 Receptor ; Dual Agonist ; Type 2 Diabetes; Peptide-1 Receptor; Spect
ISSN (print) / ISBN
2191-219X
e-ISSN
2191-219X
Journal
EJNMMI Research
Quellenangaben
Volume: 9,
Article Number: 17
Publisher
Springer
Publishing Place
Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Medicinal Chemistry (IMC)