title: N'-3-(Trifluoromethyl)phenyl Derivatives of N-Aryl-N'-methylguanidines as Prospective PET Radioligands for the Open Channel of the N-Methyl-d-aspartate (NMDA) Receptor: Synthesis and Structure-Affinity Relationships.
abstract: N-Methyl-d-aspartate (NMDA) receptor dysfunction has been linked to several neuropsychiatric disorders, including Alzheimer's disease, epilepsy, drug addiction, and schizophrenia. A radioligand that could be used with PET to image and quantify human brain NMDA receptors in the activated "open channel" state would be useful for research on such disorders and for the development of novel therapies. To date, no radioligands have shown well-validated efficacy for imaging NMDA receptors in human subjects. In order to discover improved radioligands for PET imaging, we explored structure-affinity relationships in N'-3-(trifluoromethyl)phenyl derivatives of N-aryl-N'-methylguanidines, seeking high affinity and moderate lipophilicity, plus necessary amenability for labeling with a positron-emitter, either carbon-11 or fluorine-18. Among a diverse set of 80 prepared N'-3-(trifluoromethyl)phenyl derivatives, four of these compounds (13, 19, 20, and 36) displayed desirable low nanomolar affinity for inhibition of [(3)H](+)-MK801 at the PCP binding site and are of interest for candidate 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, Maryland 20892-1003, 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, Maryland 20892-1003, United States.
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Jenko
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Building 10, Room B3 C346A, 10 Center Drive, Bethesda, Maryland 20892-1003, United States.
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Building 10, Room B3 C346A, 10 Center Drive, Bethesda, Maryland 20892-1003, United States.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Building 10, Room B3 C346A, 10 Center Drive, Bethesda, Maryland 20892-1003, 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, Maryland 20892-1003, United States.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002250:Carbon Radioisotopes; D016291:Dizocilpine Maleate / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006146:Guanidines / Q000737:chemistry* / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008024:Ligands; D008760:Methylguanidine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism; D010622:Phencyclidine / Q000378:metabolism; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D006146:Guanidines; D008024:Ligands; D009281:Naphthalenes; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate; D008760:Methylguanidine; D016291:Dizocilpine Maleate; D015057:1-Naphthylamine; D010622:Phencyclidine