|Budget Amount *help
¥3,900,000 (Direct Cost : ¥3,900,000)
Fiscal Year 1997 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1996 : ¥2,600,000 (Direct Cost : ¥2,600,000)
The object of this research is to develop PFT imaging agents selective for the open state of the NMDA ion-channel complex.We designed a lipophilic TCP analog (MMPTC) having a cis-CH_2OCH_3 group atthe C_2 of the cyclohexyl ring, and two fluorine-substituted analogs of 6,11-ethano-12,12-di(2'-thienyl) -6,11-dihydrobenzo [b]quinolizinium cation (ETDQ) which is a hydrophilic and selective openchannel NMDA receptor antagonist. ^<11>C-Labeled MMPTC was achieved by O-methylation of the hydroxy precursor with ^<11>CH_31. Brain regional distribution of ^<11>C-MMPTC in mice did not show selective accumulation in any tissues, although relatively high brain uptake was observed. The introduction of fluoroethyl substituent at C_5 on the thienyl ring of ETDQ and fluoroethoxy substituent C_8 on the benzoring of ETDQ was designed and the new synthetic routes for the prepararion of these fluorine-containing analogs, methods applicable to ^<18>F-labeling radiosynthesis, were developed. The fluoroethyl analogs showed IC_<C50> values of 47-89nM for the PCP binding site on the NMDA receptor complex, while that of the fluoroethoxy analog was 64nM,as determined by displacement of ^3H-TCP binding to rat brain homogenates. Radiosynthesis was done as a two-step, two-pot reaction sequence following these synthetic strategies. Nucleophilic ^<18>F-fluorination was carried out using the Kryptofix222/K_2CO_3 system. Cycloaddition reaction between azoniaanthracene and ^<18>F-fluorinated dithienycarbinol in CF_3CH_2OH at 80ﾟC for 30min gave the ^<18>F-fluroethyl analog in 0.5% radiochemical yield. The ^<18>F-fluoroethoxy analog wasobtained through ^<18>F-fluoroethoxylation of the hydroxy precursor in 5.5% radiochemical yield with a total synthesis time of 160 min.