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Drug Occupancy Asse...
Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography
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- Eriksson, Olof (author)
- Uppsala universitet,Theranostics,Science for Life Laboratory, SciLifeLab,Translationell avbildning med PET,Antaros Med AB, Mölndal, Sweden.;Uppsala Univ, Dept Med Chem, Sci Life Lab, Uppsala, Sweden.
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- Velikyan, Irina, 1966- (author)
- Uppsala universitet,Radiologi,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab,Translationell avbildning med PET
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- Haack, Torsten (author)
- Sanofi Aventis Deutschland GmbH, Frankfurt, Germany.
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- Bossart, Martin (author)
- Sanofi Aventis Deutschland GmbH, Frankfurt, Germany.
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- Evers, Andreas (author)
- Sanofi Aventis Deutschland GmbH, Frankfurt, Germany.
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- Lorenz, Katrin (author)
- Sanofi Aventis Deutschland GmbH, Frankfurt, Germany.
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- Laitinen, Iina (author)
- Sanofi Aventis Deutschland GmbH, Frankfurt, Germany.
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- Larsen, Philip J. (author)
- Bayer Pharmaceut, Wuppertal, Germany.
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- Plettenburg, Oliver (author)
- Helmholtz Zentrum Munchen, Munich, Germany.
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- Johansson, Lars (author)
- Antaros Med AB, Mölndal, Sweden.
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- Pierrou, Stefan (author)
- Antaros Med AB, Mölndal, Sweden.
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- Wagner, Michael (author)
- Sanofi Aventis Deutschland GmbH, Frankfurt, Germany.
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(creator_code:org_t)
- 2021-02-05
- 2021
- English.
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In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 70:4, s. 842-853
- Related links:
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https://doi.org/10.2...
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https://diabetes.dia...
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https://urn.kb.se/re...
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Abstract
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- 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 Ga-68. The resulting PET tracer [Ga-68]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [Ga-68]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [Ga-68]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 [Ga-68]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [Ga-68]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [Ga-68]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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Diabetes
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- By the author/editor
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Eriksson, Olof
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Velikyan, Irina, ...
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Haack, Torsten
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Bossart, Martin
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Evers, Andreas
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Lorenz, Katrin
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show more...
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Laitinen, Iina
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Larsen, Philip J ...
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Plettenburg, Oli ...
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Johansson, Lars
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Pierrou, Stefan
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Wagner, Michael
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Diabetes
- By the university
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Uppsala University