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.
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.
Haradahira
Terushi
T
Department of Medical Imaging, National Institute of Radiological Sciences, Chiba 263-8555, Japan. terushi@nirs.go.jp
Maeda
Jun
J
Okauchi
Takashi
T
Zhang
Ming-Rong
MR
Hojo
Junko
J
Kida
Takayo
T
Arai
Takuya
T
Yamamoto
Fumihiko
F
Sasaki
Shigeki
S
Maeda
Minoru
M
Suzuki
Kazutoshi
K
Suhara
Tetsuya
T
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
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