TY - JOUR

T1 - First-in-class positron emission tomography tracer for the glucagon receptor

AU - Velikyan, Irina

AU - Haack, Torsten

AU - Bossart, Martin

AU - Evers, Andreas

AU - Laitinen, Iina

AU - Larsen, Philip

AU - Plettenburg, Oliver

AU - Johansson, Lars

AU - Pierrou, Stefan

AU - Wagner, Michael

AU - Eriksson, Olof

N1 - Funding Information: Dr. Mohamed Altai is acknowledged for valuable discussions. We also thank R. Loder, R. Micciche, S. Rauch, A. Sadikovic, K. Schlitt, C. Schneider, M. Schnierer, and L. Wäß for compound synthesis during the optimization program, M. Schaffrath and team for peptide purification and Sigi Stengelin for the in vitro results from over-expressing cell lines. The study was sponsored in full by Sanofi. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

PY - 2019/2/15

Y1 - 2019/2/15

N2 - 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.

AB - 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.

KW - Dual agonist

KW - GCG

KW - GLP-1 receptor

KW - Glucagon

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85061628988&partnerID=8YFLogxK

U2 - 10.1186/s13550-019-0482-0

DO - 10.1186/s13550-019-0482-0

M3 - Article

AN - SCOPUS:85061628988

VL - 9

JO - EJNMMI Research

JF - EJNMMI Research

SN - 2191-219X

M1 - 17

ER -