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

开发用于评估 NMDA 受体功能的正电子标记放射性示踪剂

基本信息

批准号：
08457244
负责人：
MAEDA Minoru
金额：
$ 2.5万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

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.

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) -6,11-二氢苯并[b] quinolizinium阳离子（ETDQ），它是一种亲水和选择性的开频道NMDA接收器拮抗剂。 ^<11> C标记的MMPTC是通过用 ^<11> CH_31的羟基前体O-甲基化来实现的。尽管观察到相对较高的大脑摄取，但在小鼠中 ^<11> c-MMPTC的大脑区域分布尚未显示出选择性的积累。设计了ETDQ和氟乙氧基纤维纤维subtituent C_8在ETDQ苯基上的硫烯基环的引入C_5的引入，并设计了用于制备这些含碳类似物的新合成途径，适用于 ^<18> f-flabeling放射性的方法。 NMDA受体复合物上的PCP结合位点的IC_ <c50>的氟乙基类似物的值为47-89nm，而氟乙氧基类似物的含量为64nm，这是通过位移 ^3H-TCP与大鼠脑染料结合的 ^3H-TCP确定的。遵循这些合成策略的两步，两杆反应序列进行了放射合成。使用Kryptofix222/k_2co_3系统进行了亲核 ^<18> F-氟化。偶氮氨基氨基烯和 ^<18> f氟氟二硫酸二硫酸苯酚在CF_3CH_2OH中为30分钟的二硫酸二硫酸苯酚之间的环反应给出了0.5％放射化学产量的 ^<18> f-fluoroethyl类似物。通过 ^<18> f氟乙氧基类似物通过5.5％放射化学产率的羟基前体的 ^<18> F-氟乙氧基化，总合成时间为160分钟。