title: Synthesis and receptor binding studies of (+/-)1-iodo-MK-801.
abstract: The glutamate analogue N-methyl-D-aspartate (NMDA) binds to a subset of glutamate receptors that are coupled to a voltage-sensitive cation channel. This NMDA-linked channel is the likely binding locus of the potent anticonvulsant MK-801. To develop single-photon emission computed tomography (SPECT) probes of this brain channel, we synthesized (+/)1-iodo-MK-801 and (+/-)1-[125I]iodo-MK-801. The effect of (+/-)1-iodo-MK-801 on ligand binding to the NMDA-linked glutamate receptor site was assessed using a rat brain homogenate assay. (+/-)1-Iodo-MK-801 displaced the dissociative anesthetic ligand [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding with an IC50 of 1 microM, which is a 10-fold lower binding affinity than that of (+/-)MK-801. In in vivo autoradiographic studies, (+/-)MK-801 failed to block selective uptake of (+/-)1-iodo-MK-801 in rat brain. These results suggest that (+/-)1-iodo-MK-801 may not be a suitable ligand for mapping NMDA-linked glutamate receptor channels.
authors.affiliation: Department of Nuclear Medicine, University of Michigan Medical School, Ann Arbor 48109.
authors.forename: D J
authors.initials: DJ
authors.lastname: Yang
authors.forename: B J
authors.initials: BJ
authors.lastname: Ciliax
authors.forename: M E
authors.initials: ME
authors.lastname: Van Dort
authors.forename: D
authors.initials: D
authors.lastname: Gildersleeve
authors.forename: J L
authors.initials: JL
authors.lastname: Pirat
authors.forename: A B
authors.initials: AB
authors.lastname: Young
authors.forename: D M
authors.initials: DM
authors.lastname: Wieland
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000493:pharmacokinetics; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001345:Autoradiography; D001923:Brain Chemistry; D003986:Dibenzocycloheptenes / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics; D016291:Dizocilpine Maleate / Q000031:analogs & derivatives; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008297:Male; D016202:N-Methylaspartate; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D007457:Iodine Radioisotopes; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C060703:1-iodo-MK 801; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate