title: Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain.
abstract: Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer's disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a-c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [124/125I]4d and [11C]4e (i.e., [124/125I]11d and [11C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [125I]11d and [11C]11e through autoradiography and biodistribution studies, imaging of neither [124I]11d nor [11C]11e could demonstrate brain penetration sufficient for detection by PET.
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School , Baltimore, Maryland 21287, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School , Baltimore, Maryland 21287, United States.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Foss
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School , Baltimore, Maryland 21287, United States.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
authors.affiliation: Department of Pharmacology, Emory University School of Medicine , Atlanta, Georgia 30322, United States.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School , Baltimore, Maryland 21287, United States.
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.affiliation: Department of Biomedical & Pharmaceutical Sciences, University of Montana , 32 Campus Drive, Missoula, Montana 59812, United States.
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Paola
authors.identifier: 0000-0003-2140-0567
authors.initials: P
authors.lastname: Conti
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School , Baltimore, Maryland 21287, United States.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000737:chemistry*; D007457:Iodine Radioisotopes; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology; D000072078:Positron Emission Tomography Computed Tomography; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis*; D013329:Structure-Activity Relationship
chemical_list: D002250:Carbon Radioisotopes; D007457:Iodine Radioisotopes; D008024:Ligands; D018696:Neuroprotective Agents; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid