First-in-class positron emission tomography tracer for the glucagon receptor
Creators: name: Velikyan, Irina
name: Haack, Torsten
name: Bossart, Martin
name: Evers, Andreas
name: Laitinen, Ilina
name: Larsen, Philip
name: Plettenburg, Oliver
name: Johansson, Lars
name: Pierrou, Stefan
name: Wagner, Michael
name: Eriksson, Olof
Publisher: name: Heidelberg : Springer Verlag
Year: 2019
Subjects: subject: Dual agonist
subject: GCG
subject: GLP-1 receptor
subject: Glucagon
subject: Type 2 diabetes
subject: antidiabetic agent
subject: cysteine
subject: exendin 4
subject: Ga DO3A S01 GCG
subject: Ga DO3A S02 GCG
subject: gadoteridol
subject: gallium 68
subject: glucagon like peptide 1
subject: glucagon like peptide 1 receptor agonist
subject: glucagon receptor
subject: glucagon receptor agonist
subject: peptide
subject: phosphorus
subject: radioisotope
subject: radiopharmaceutical agent
subject: tracer
subject: unclassified drug
subject: adult
subject: animal model
subject: autoradiography
subject: binding affinity
subject: body weight
subject: body weight loss
subject: cAMP assay
subject: carboxy terminal sequence
subject: controlled study
subject: dosimetry
subject: effective dose (radiation)
subject: female
subject: gene overexpression
subject: HEK293 cell line
subject: high performance liquid chromatography
subject: human
subject: human cell
subject: human tissue
subject: internalization
subject: isotope labeling
subject: liver biopsy
subject: liver tissue
subject: male
subject: nonhuman
subject: positron emission tomography
subject: priority journal
subject: quality control
subject: radioactivity
subject: radiochemistry
subject: rat
subject: receptor affinity
subject: receptor occupancy
subject: retention time
subject: Dewey Decimal Classification::600 | Technik::610 | Medizin, Gesundheit

description: 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 [ 68 Ga]Ga-DO3A-S01-GCG and [ 68 Ga]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: [ 68 Ga]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. [ 68 Ga]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: [ 68 Ga]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.