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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457244/
• 关键词: NMDA Receptor; In-Vivo Ligand; Fluorine-18; Carbon-11; Labeling Synthesis; Azoniaanthracene; TCP; 標識合成; ラジオリガンド; イメージング

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.

本研究的目的是开发对NMDA离子通道复合物开放状态具有选择性的PFT显像剂。我们设计了一种在环己基环的C_2处具有顺式CH_2OCH_3基团的亲脂性TCP类似物(MMPTC)，以及两种氟取代的6,11-ethano-12,12-di(2'-thienyl)类似物 -6,11-二氢苯并[b]喹嗪鎓阳离子 (ETDQ) 是一种亲水性、选择性开放通道 NMDA 受体拮抗剂。 11 C标记的MMPTC是通过用11 CH_31对羟基前体进行O-甲基化来实现的。小鼠中11 C-MMPTC的脑区域分布没有显示出在任何组织中的选择性积累，尽管观察到相对较高的脑摄取。设计了在ETDQ的噻吩环C_5上引入氟乙基取代基和在ETDQ的苯并环上引入氟乙氧基取代基C_8，并开发了制备这些含氟类似物的新合成路线，以及适用于^ 18 F标记放射合成的方法。氟乙基类似物显示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，如通过与大鼠脑匀浆结合的3H-TCP的置换所测定。放射合成按照这些合成策略以两步、两锅反应顺序进行。使用Kryptofix222/K_2CO_3系统进行亲核18 F-氟化。氧化氮蒽和^ 18 F-氟化二噻吩基甲醇在CF_3CH_2OH中于80℃下进行环加成反应30分钟，得到^ 18 F-氟乙基类似物，放射化学产率为0.5％。通过羟基前体的18 F-氟乙氧基化获得18 F-氟乙氧基类似物，总合成时间为160分钟，放射化学产率为5.5％。