Details
| Original language | English |
|---|---|
| Pages (from-to) | 842-853 |
| Number of pages | 12 |
| Journal | DIABETES |
| Volume | 70 |
| Issue number | 4 |
| Early online date | 5 Feb 2021 |
| Publication status | Published - 19 Apr 2021 |
| Externally published | Yes |
Abstract
Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic 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 68Ga. 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 were assessed in nonhuman primates (NHPs) by PET. [68Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment 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, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
ASJC Scopus subject areas
- Medicine(all)
- Internal Medicine
- Medicine(all)
- Endocrinology, Diabetes and Metabolism
Sustainable Development Goals
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In: DIABETES, Vol. 70, No. 4, 19.04.2021, p. 842-853.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography
AU - Eriksson, Olof
AU - Velikyan, Irina
AU - Haack, Torsten
AU - Bossart, Martin
AU - Evers, Andreas
AU - Lorenz, Katrin
AU - Laitinen, Iina
AU - Larsen, Philip J.
AU - Plettenburg, Oliver
AU - Johansson, Lars
AU - Pierrou, Stefan
AU - Wagner, Michael
N1 - Funding information: The authors thank Dr. Tim Klöckner (Sanofi) for testing relevant compounds in displacement assays with [125I]GIP using membranes from huGIPR-HEK293 cells as well as Dr. Ziu Li (Sanofi) for testing relevant compounds in functional cAMP assays in HEK293 cells. The Preclinical PET/MRI Platform at Uppsala University is acknowledged for providing expertise, instrumentation, and facilities for PET tracer evaluation.
PY - 2021/4/19
Y1 - 2021/4/19
N2 - Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic 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 68Ga. 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 were assessed in nonhuman primates (NHPs) by PET. [68Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment 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, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
AB - Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic 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 68Ga. 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 were assessed in nonhuman primates (NHPs) by PET. [68Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment 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, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
UR - http://www.scopus.com/inward/record.url?scp=85103306511&partnerID=8YFLogxK
U2 - 10.2337/db20-1096
DO - 10.2337/db20-1096
M3 - Article
C2 - 33547046
AN - SCOPUS:85103306511
VL - 70
SP - 842
EP - 853
JO - DIABETES
JF - DIABETES
SN - 0012-1797
IS - 4
ER -