title: New N-aryl-N'-(3-(substituted)phenyl)-N'-methylguanidines as leads to potential PET radioligands for imaging the open NMDA receptor.
abstract: 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 positron-emitter, carbon-11 (t1/2=20.4min). 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; Ki 36.7nM), 3'-trifluoromethyl (20; Ki 18.3nM) and 3'-methylthio (2; Ki 39.8nM) derivatives of N-1-naphthyl-N'-(phenyl)-N'-methylguanidine were identified as especially attractive leads for PET radioligand development.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Naumiec
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Cai
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States. Electronic address: pikev@mail.nih.gov.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D001665:Binding Sites / Q000502:physiology; D008760:Methylguanidine / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011868:Radioisotopes / Q000737:chemistry* / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D011868:Radioisotopes; D016194:Receptors, N-Methyl-D-Aspartate; D008760:Methylguanidine
keywords: N-Methyl-d-aspartate receptor; Phencyclidine; Positron emission tomography