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Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography.

Authors :
Taddio MF
Mu L
Castro Jaramillo CA
Bollmann T
Schmid DM
Muskalla LP
Gruene T
Chiotellis A
Ametamey SM
Schibli R
Krämer SD
Source :
Journal of medicinal chemistry [J Med Chem] 2019 Sep 12; Vol. 62 (17), pp. 8090-8100. Date of Electronic Publication: 2019 Aug 29.
Publication Year :
2019

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, [ <superscript>11</superscript> C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [ <superscript>11</superscript> 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.

Details

Language :
English
ISSN :
1520-4804
Volume :
62
Issue :
17
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
31430137
Full Text :
https://doi.org/10.1021/acs.jmedchem.9b00858