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

He, Yingfang and Whitehead, David and Briard, Emmanuelle and Numao, Shin and Mu, Linjing and Schibli, Roger and 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


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