New N-aryl-N′-(3-(substituted)phenyl)-N′-methylguanidines as leads to potential PET radioligands for imaging the open NMDA receptor (original) (raw)

An expansive set of N-aryl-N'-(3-(substituted)phenyl)-N'-methylguanidines was prepared in a search for new leads to prospective PET ligands for imaging of the open channel of the N-methyl-D-aspartate (NMDA) receptor in vivo. The N-aryl rings and their substituents were varied, whereas the N-methyl group was maintained as a site for potential labeling with the positronemitter, carbon-11 (t 1/2 = 20.4 min). At micromolar concentration, over half of the prepared compounds strongly inhibited the binding of [ 3 H]TCP to its binding site in the open NMDA receptor in vitro. Four ligands displayed affinities that are similar or superior to those of the promising SPECT radioligand ([ 123 I]CNS1261). The 3'-dimethylamino (19; K i 36.7 nM), 3'trifluoromethyl (20; K i 18.3 nM) and 3'-methylthio (2; K i 39.8 nM) derivatives of N-1-naphthyl-N'-(phenyl)-N'-methylguanidine were identified as especially attractive leads for PET radioligand development.