Evaluation of 5H‐Thiazolopyrimidin‐5‐ones as Potential GluN2A PET Tracers

• Published in: ChemMedChem Vol. 15; no. 24; pp. 2448 - 2461
• Main Authors: He, Yingfang, Whitehead, David M, Briard, Emmanuelle, Shin Numao, Mu, Linjing, Schibli, Roger, Ametamey, Simon M, Auberson, Yves P
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 01.12.2020
• Subjects: Allosteric properties; Autoradiography; Binding; Cyclopropane; Dimers; Glutamic acid receptors (ionotropic); Image quality; Modulators; N-Methyl-D-aspartic acid receptors; Optimization; Organic compounds; Positron emission; Receptors; Tomography; Tracers
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202000340

We describe here our efforts to develop a PET tracer for imaging GluN2A‐containing NMDA receptors, based on a 5H‐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‐5H‐thiazolo‐[3,2‐α]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‐α]pyrimidin‐3‐yl)cyclopropane‐1‐carbonitrile ([3H2]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.