DEVELOPMENT OF RADIOPHARMACEUTICALS FOR IMAGING THE NMDA RECEPTOR FUNCTIONS

用于 NMDA 受体功能成像的放射性药物的开发

• 批准号: 06453183
• 负责人: MAEDA Minoru
• 金额: $ 1.79万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06453183/
• 关键词: NMDA receptors; TCP; Fluorine-18; ^<18>F-Labelled ligands; Nuclear imaging agents; 核医学診断薬; チェニルシクロヘキシルピペリジン; 標識合成

There has been great interest in the development of useful radioligands for imaging the NMDA receptor in living human brain by non-invasive tomographic techniques. New fluorine-18 labelled derivatives of thienylcyclohexylpiperidine (TCP), a noncompetitive antagonist of NMDA receptor, which binds to the phencyclidine (PCP) binding site located within the receptor-associated ion channel, have been synthesized. The mesylate precursors for (1S^*,2R^*) -2- (hydroxymethyl) -and (1S^*,2R^*) -2- (methoxymethoxymethyl) -1- (N-piperidyl) -1- [2- (2'-[^<18>F] fluoroethyl) thiophenyl] cyclohexane, respectively, were prepared from 2-hydroxycyclohexanone. Radiochemical syntheses were done by displacement of the mesylates by [^<18>F] fluoride ion with no-carrier-added [K/2.2.2] ^<+18>F in 4-4.5%radiochemical yields with specific activity of>31GBq/mol. In the biodistribution studies with these ^<18>F-radioligands, no specifc accumulation of radioactivity was observed and blocking effect of 1- [1- (2-thienyl) -2-hydroxy-methylcyclohexyl] piperidine (cis-HPTC) was not found for all the tissues investigated, clearly indicating that the radioactivity was distributed due to non-selective binding. Low affinities of these ligands to the NMDA receptor were also shown in vitro binding experiemnts. ln conclusion, it turned out that the new ligands were not suitable as in vivo radioligands for PET studies of NMDA receptor. lt will be necessary to use more hydrophilic molecules as lead compounds for developing useful in vivo radioligands for NMDA receptor.

人们对通过非侵入性层析成像技术在生命的人脑中成像有用的放射性物体引起了极大的兴趣。已合成了新的NMDA受体的非竞争性拮抗剂硫己己基磷酸氨基胺（TCP）的新型氟-18标记的衍生物，该氟己糖基哌啶（TCP）已被合成。 （1s^*，2r^*）-2-（羟基甲基） - 和（1S^*，2R^*）-2-（甲氧甲基甲氧基）-1-（n-piperidyl）-1-（N-甲氧基）-1-（2' - （2' - [2'- [^ - [^ - [^^<18> f]氟乙基）thiophophaneyyy cycane cycane cycane cycane cycane， 2-羟基环己酮。通过[ ^<18> f]氟离子将梅赛替换为未载体的[K/2.2.2] ^<+18> F中的[ ^<18> f]氟离子以4-4.5％放射化学产率中的[ ^<18> f]氟化离子的位移来完成放射化学合成。在对这些 ^<18> F-亚adiolig体的生物分布研究中，未观察到放射性的特定积累，1- [1-（2-硫烯基）-2-羟基 - 甲基环己基]哌啶]哌啶（CIS-HPTC）的阻塞效应并未在所有组织中均能分配给出的所有组织。在体外结合体验中，这些配体与NMDA受体的亲和力也低。得出结论，事实证明，新的配体不适合用于NMDA受体的PET研究的体内放射线。 LT将有必要使用更多的亲水分子作为铅化合物，以开发用于NMDA受体的体内放射性物体。

项目成果

Y. Shibayama, S. Sasaki, U. Tomita, T. Nishikawa and M. Maeda: "Synthesis and Evaluation of New ^<18>F-Labelled Thienylcyclohexylpiperidine(TCP) Analogues as Radioligands for the NMDA Receptor-Channel Complex" J. Labelled Compounds Radiopharmaceuticals. 3

Y. Shibayama、S. Sasaki、U. Tomita、T. Nishikawa 和 M. Maeda：“作为 NMDA 受体通道复合物放射性配体的新型 18 F 标记噻吩基环己基哌啶 (TCP) 类似物的合成和评估” J.

Y.Shibayama: "Synthesis and Evaluation of New ^<18>F-Labelled Thienylcyclohexylpiperidine (TCP) Analogues as Radioligands for the NMDA Receptor-Channel Complex" J.Labelled Compounds Radiopharm.38 (1). 77-86 (1996)

Y.Shibayama：“作为NMDA受体通道复合物的放射性配体的新型18F标记的噻吩基环己基哌啶(TCP)类似物的合成和评价”J.LabeledCompoundsRadiopharm.38(1)。

Y. Shibayama: "Synthesis and Evaluation of New ^<18>F-Labelled Thienylcyclohexylpiperidine (TCP) Analogues as Padioligands for the NMDA Receptor-Channel Complex" J. Labelled Compounds Radiopharm.38. 77-86 (1996)

Y. Shibayama：“作为NMDA受体通道复合物的Padioligands的新型18 F标记的噻吩基环己基哌啶(TCP)类似物的合成和评估”J.标记化合物Radiopharm.38。