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Evaluation of 5 H ‐Thiazolo[3,2‐α]pyrimidin‐5‐ones as Potential GluN2A PET Tracers
Author(s) -
He Yingfang,
Whitehead David M.,
Briard Emmanuelle,
Numao Shin,
Mu Linjing,
Schibli Roger,
Ametamey Simon M.,
Auberson Yves P.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000340
Subject(s) - radioligand , chemistry , nmda receptor , pharmacophore , radioligand assay , stereochemistry , ligand (biochemistry) , allosteric regulation , ex vivo , in vivo , receptor , biochemistry , in vitro , biology , microbiology and biotechnology
We describe here our efforts to develop a PET tracer for imaging GluN2A‐containing NMDA receptors, based on a 5 H ‐thiazolo[3,2‐α]pyrimidin‐5‐one scaffold. The metabolic stability and overall properties could be optimized satisfactorily, although binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7‐(((2‐fluoroethyl)(3‐fluorophenyl)amino)‐methyl)‐3‐(2‐(hydroxymethyl)cyclopropyl)‐2‐methyl‐5 H ‐thiazolo‐[3,2‐α]pyrimidin‐5‐one ([ 18 F] 7b ) as a radioligand providing good‐quality images in autoradiographic studies, as well as a tritiated derivative, 2‐(7‐(((2‐fluoroethyl)(4‐fluorophenyl)amino)methyl)‐2‐methyl‐5‐oxo‐5 H ‐thiazolo[3,2‐α]pyrimidin‐3‐yl)cyclopropane‐1‐carbonitrile ([ 3 H 2 ] 15b ), which was used for the successful development of a radioligand binding assay. These are valuable new tools for the study of GluN2A‐containing NMDA receptors, and for the optimization of allosteric modulators binding to the pharmacophore located at the dimer interface of the GluN1‐GluN2A ligand‐binding domain.