PuSH - Publication Server of Helmholtz Zentrum München: Drug occupancy assessment at the glucose-dependent insulinotropic polypeptide (GIP) receptor by positron emission tomography.

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

Drug occupancy assessment at the glucose-dependent insulinotropic polypeptide (GIP) receptor by positron emission tomography.

Diabetes 70, 842-853 (2021)

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Targeting of the Glucose-dependent Insulinotropic Polypeptide receptor GIPR is an emerging strategy in anti-diabetic drug development. The aim of this study was to develop a Positron Emission Tomography (PET) radioligand for the GIPR, to enable the assessment of target distribution and drug target engagement in vivo.The GIPR selective peptide S02-GIP was radiolabeled with Gallium-68. The resulting PET tracer [⁶⁸Ga]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [⁶⁸Ga]S02-GIP-T4, as well as the occupancy of a drug candidate with GIPR activity, was assessed in non-human primates (NHP) by PET.[⁶⁸Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo pancreatic binding in NHP could be dose dependently inhibited by co-injection of unlabelled S02-GIP-T4. Finally, subcutaneous pre-treatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [⁶⁸Ga]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [⁶⁸Ga]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [⁶⁸Ga]S02-GIP-T4 is a novel PET biomarker for safe, non-invasive, and quantitative assessment of GIPR target distribution and drug occupancy.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

ISSN (print) / ISBN 0012-1797

e-ISSN 1939-327X

Journal Diabetes

Quellenangaben Volume: 70, Issue: 4, Pages: 842-853

Publisher American Diabetes Association

Publishing Place Alexandria, VA.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Medicinal Chemistry (IMC)

Grants 125I