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离子通道复合体开放状态的PFT显像剂。我们设计了一个在环己环的C_2上带有顺-CH_2OCH_3基团的亲脂性的TCP类似物(MMPTC)和两个氟取代的类似物6，11-乙基-12，12-二(2‘-噻吩基)-6，11-二氢苯并[b]喹啉基阳离子(ETDQ)，它是一种亲水性的选择性开放通道NMDA受体拮抗剂。^&lt；11&gt；C标记的MMPTC是通过羟基前体与^&lt；11&gt；CH_31进行O-甲基化得到的。尽管观察到相对较高的脑摄取，但^&lt；11&gt；C-MMPTC在小鼠脑内的区域分布在任何组织中都没有显示出选择性蓄积。设计了在ETDQ的硫烯基环上引入C_5氟乙基取代基和在ETDQ的苯偶联反应上引入C_8氟乙氧基取代基的方法，为这些含氟类似物的制备开辟了新的合成路线，并提出了适用于放射性合成的方法。氟乙基类似物显示NMDA受体复合体上PCP结合部位的IC值为47-89 nM，而氟乙氧基类似物的IC值为64 nM，这是通过~3H-TCP与大鼠脑匀浆结合的位移确定的。放射合成是按照这些合成策略进行的两步、两锅反应序列。亲核氟化反应是用氪222/K_2CO_3体系进行的。偶氮并菲与氟代二硫代甲醇在Cf_3CH_2OH中于80ﾟ℃反应30min，得到β&lt；18；F-氟乙基类似物，放化产率为0.5%。羟基前体经氟乙氧基化反应制得氟乙氧基类似物，放化产率为5.5%，总合成时间为160分钟。

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.