Development of Positron-Labeled Radiotracers for Evaluation of NMDA Receptor Functions

本研究设计了一种亲脂性TCP类似物（MMPTC）和两个氟取代的6，11-乙-12，12-二氨基-1，2，3，4-四氢呋喃类似物（6，11-ethano-12，12-di-1，2，3，4，5-dichloroethanol，6，11-ethanol，6，12-dichloroethanol，6，11-ethanol，6，1（2 '-噻吩基）-6，11-二氢苯并[B]喹嗪鎓阳离子（ETDQ），是一种亲水性和选择性的开放通道NMDA受体拮抗剂。通过<11>羟基前体与^CH_31的O-甲基化获得^C-标记的MMPTC<11>。小鼠脑内α-C-MMPTC的区域分布<11>未显示在任何组织中的选择性蓄积，尽管观察到相对较高的脑摄取。设计了在ETDQ噻吩环C_5位引入氟乙基取代基和在ETDQ苯并环C_8位引入氟乙氧基取代基的方法，发展了这些含氟类似物的合成新路线，为~（12<18>）F标记放射合成提供了新的方法。氟代乙基类似物对<C50>NMDA受体复合物上PCP结合位点的IC值为47- 89 nM，而氟代乙氧基类似物的IC值为64 nM，这是通过取代^3 H-TCP与大鼠脑匀浆的结合测定的。按照这些合成策略，放射合成作为两步、两锅反应序列进行。用<18>Kryptofix 222/K_2CO_3体系进行亲核性~（12）F-双反硝化。在CF_3CH_2OH中，氮鎓蒽与~ 4F<18>-氟代二噻吩甲醇在80 ℃下环加成30 min，得到~ <18>4F-氟乙基类似物，放化产率为0.5%。通过羟基前体的^<18>F-氟乙氧基化得到^F-氟乙氧基类似物<18>，放射化学产率为5.5%，总合成时间为160 min。

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.