Evaluation of 5H-Thiazolo[3,2-α]pyrimidin-5-ones as Potential GluN2A PET Tracers |
| |
Authors: | Yingfang He Dr David M Whitehead Dr Emmanuelle Briard Dr Shin Numao Dr Linjing Mu Prof Roger Schibli Prof Simon M Ametamey Dr Yves P Auberson |
| |
Affiliation: | 1. Department of Chemistry and Applied Biosciences ETH Zürich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland;2. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Fabrikstrasse 2, 4056 Basel, Switzerland;3. Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Fabrikstrasse 2, 4056 Basel, Switzerland |
| |
Abstract: | We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on a 5H-thiazolo3,2-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-thiazolo3,2-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. |
| |
Keywords: | receptor imaging agent radiochemistry NMDA defluorination |
|
|