title: (+)-3-[123I]Iodo-MK-801: synthesis and characterization of binding to the N-methyl-D-aspartate receptor complex.
abstract: Synthetic methods have been established for preparing high specific activity (+)-3-[123I]Iodo-MK-801 in high radiochemical yield. The binding of the radiotracer to rat cortical membranes has been examined to assess its potential use as an in vivo imaging agent for the N-methyl-D-aspartate (NMDA) receptor-ion channel complex. Under the conditions of the assay, specific (+)-3-[123I]Iodo-MK-801 binding to membrane homogenates represented greater than 95% of the total binding. Several structurally distinct, noncompetitive NMDA receptor antagonists inhibited binding with potencies in accordance with their reported inhibitory activity at the receptor complex. The concentration of (+/-)-3-Iodo-MK-801 required to inhibit 50% of (+)-3-[123I]Iodo-MK-801 binding (IC50) was 3.4 nM when using a low ionic strength assay buffer and 5.5 nM in a physiological buffer. In a thoroughly washed membrane preparation, (+)-3-[123I]Iodo-MK-801 binding was enhanced by L-glutamate and glycine at concentrations known to activate the NMDA receptor. The results indicate that (+)-3-[123I]Iodo-MK-801 specifically labels the NMDA receptor complex in rat brain membranes and the retention of high affinity under near physiological assay conditions suggests that it may be useful as a SPECT imaging agent for the receptor in vivo.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
authors.forename: R W
authors.initials: RW
authors.lastname: Ransom
authors.forename: W S
authors.initials: WS
authors.lastname: Eng
authors.forename: H D
authors.initials: HD
authors.lastname: Burns
authors.forename: R E
authors.initials: RE
authors.lastname: Gibson
authors.forename: H F
authors.initials: HF
authors.lastname: Solomon
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D003986:Dibenzocycloheptenes / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000031:analogs & derivatives*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D003986:Dibenzocycloheptenes; D007457:Iodine Radioisotopes; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; C031959:aspartic acid receptor; C060703:1-iodo-MK 801; D016291:Dizocilpine Maleate