title: Synthesis, in vitro and in vivo pharmacology of a C-11 labeled analog of CP-101,606, (+/-)threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[11C]methoxyphenyl)piperidino]-1-propanol, as a PET tracer for NR2B subunit-containing NMDA receptors.
abstract: A carbon-11 labeled methoxyl analog of CP-101,606, (+/-)threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[11C]methoxyphenyl)piperidino]-1-propanol [(+/-)[11C]1], was synthesized as a new subtype-selective PET radioligand for NMDA receptors. The in vitro binding studies using rat brain slices demonstrated that (+/-)[11C]1 shows an extremely high-specific binding to the NR2B subunit of NMDA receptors. In contrast to the in vitro binding, the in vivo binding to mouse and monkey brains showed no apparent specific localization of the radioactivity in any of the brain regions. Metabolism and physicochemical properties such as the lipophilicity of (+/-)[11C]1 seemed unlikely to affect the in vivo (+/-)[11C]1 binding. Among the various endogenous ligands acting at the NMDA receptors, polyamines (spermine and spermidine) and divalent cations (Mg(2+,) Zn(2+,) and Ca(2+)) strongly inhibited the in vitro (+/-)[11C]1 binding. Thus, the present studies point to the possibility that the polyamines and cations behave as endogenous inhibitors for (+/-)[11C]1 binding, leading to the loss of the specific binding in vivo.
authors.affiliation: Department of Medical Imaging, National Institute of Radiological Sciences, Chiba 263-8555, Japan. terushi@nirs.go.jp
authors.forename: Terushi
authors.initials: T
authors.lastname: Haradahira
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Junko
authors.initials: J
authors.lastname: Hojo
authors.forename: Takayo
authors.initials: T
authors.lastname: Kida
authors.forename: Takuya
authors.initials: T
authors.lastname: Arai
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yamamoto
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Maeda
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008251:Macaca; D008297:Male; D008670:Metals / Q000494:pharmacology; D051379:Mice; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013096:Spermine / Q000494:pharmacology; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014915:Whole-Body Counting
chemical_list: D002250:Carbon Radioisotopes; D008670:Metals; C121001:NR2B NMDA receptor; D010880:Piperidines; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; C095106:traxoprodil mesylate; C010739:ifenprodil