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

He, Yingfang, Whitehead, David, Briard, Emmanuelle, Numao, Shin, Mu, Linjing, Schibli, Roger, Ametamey, Simon and Auberson, Yves (2020) Evaluation of 5H-thiazolo[3,2-alpha]pyrimidin-5-ones as potential GluN2A PET tracers. ChemMedChem : chemistry enabling drug discovery, 15 (24). pp. 2448-2461. ISSN 1860-71791860-7187


We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on 5H-thiazolo[3,2-]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-5H-thiazolo-[3,2-a]pyrimidin-5-one ([18F]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-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([3H]11a), 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.

Item Type: Article
Keywords: NMDA; PET Imaging; GluN2A
Date Deposited: 16 Jan 2021 00:45
Last Modified: 16 Jan 2021 00:45