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Synthesis and structure-affinity relationship of small molecules for imaging human CD80 by positron emission tomography


Taddio, Marco F; Mu, Linjing; Castro Jaramillo, Claudia A; Bollmann, Tanja; Schmid, Dominik M; Muskalla, Lukas P; Gruene, Tim; Chiotellis, Aristeidis; Ametamey, Simon M; Schibli, Roger; Krämer, Stefanie D (2019). Synthesis and structure-affinity relationship of small molecules for imaging human CD80 by positron emission tomography. Journal of Medicinal Chemistry, 62(17):8090-8100.

Abstract

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure-affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, [$^{11}$C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [$^{11}$C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.

Abstract

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure-affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, [$^{11}$C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [$^{11}$C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nuclear Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:12 September 2019
Deposited On:05 Feb 2020 18:51
Last Modified:05 Feb 2020 18:52
Publisher:American Chemical Society (ACS)
ISSN:0022-2623
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.jmedchem.9b00858
PubMed ID:31430137

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