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

本研究的目的是开发选择性的NMDA离子通道复合物开放状态的PFT显像剂。我们设计了一个亲脂性的TCP类似物（MMPTC），在环己基环的C_2上有一个顺式ch_2och_3基团，以及两个氟取代的6,11-乙醇-12,12-二（2'-噻吩基）-6,11-二氢苯并[b]喹啉化阳离子（ETDQ），这是一种亲水的选择性开放通道NMDA受体拮抗剂。^<11> c -标记的MMPTC是通过羟基前体与^<11>CH_31的o -甲基化获得的。^<11 b> C-MMPTC在小鼠的脑区域分布没有在任何组织中表现出选择性积累，尽管观察到相对较高的脑摄取。设计了在ETDQ的噻吩环C_5处引入氟乙基取代基，并在ETDQ的苯并化上引入氟乙氧基取代基C_8，为制备这些含氟类似物开辟了新的合成路线，开发了适用于^<18> f标记放射性合成的方法。氟乙基类似物在NMDA受体复合物上的PCP结合位点的IC_<C50>值为47-89nM，而氟乙氧基类似物的IC_<C50>值为64nM，这是通过取代^3H-TCP结合到大鼠脑浆液来确定的。放射性合成是按照这些合成策略进行的两步，两锅反应序列。采用Kryptofix222/K_2CO_3体系进行亲核氟化反应。在CF_3CH_2OH中，偶氮蒽与<18>氟化二硫代甲醇在80℃下反应30min，得到<18>氟化二硫代甲醇类似物，放射化学产率为0.5%。通过对羟基前体进行^<18> f -氟乙氧基化，得到^<18> f -氟乙氧基类似物，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.