Evaluation of 5H-thiazolo[3,2-a]pyrimidin-5-ones as potential GluN2A PET tracers.

We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on 5 H -thiazolo[3,2-a]pyrimidin-5-one scaffold. Metabolic stability and overall properties could be optimized satisfactorily, while 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-a]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-a]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([ 3 H 2 ] 11b ), 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.
PMID: 32544308 [PubMed - as supplied by publisher]

Source: ChemMedChem - June 15, 2020 Category: Chemistry Authors: He Y, Whitehead D, Briard E, Numao S, Mu L, Schibli R, Ametamey S, Auberson YP Tags: ChemMedChem Source Type: research