DEVELOPMENT OF RADIOPHARMACEUTICALS FOR IMAGING THE NMDA RECEPTOR FUNCTIONS

通过非侵入性断层扫描技术，开发用于活体人脑中NMDA受体成像的有用的放射性配体已经引起了极大的兴趣。合成了新的噻吩环己基哌啶（TCP）的氟-18标记衍生物，TCP是一种非竞争性NMDA受体拮抗剂，它与受体相关离子通道中的苯环利定（PCP）结合位点结合。以2-羟基环己酮为原料，分别制备了（1 S ^*，2 R ^*）-2-（羟甲基）-环己烷和（1 S ^*，2 R ^*）-2-（甲氧基甲氧基甲基）-1-（N-哌啶基）-1- [2-（2 '-[<18>2F]氟乙基）噻吩基]环己烷的甲磺酸酯前体。在<18>不加载体的[K/2.2.2] ^+18&gt;F条件下，用[^ F]氟离子置换甲磺酸酯进行放化合成，放化产率为4- 4.5%，比活度&gt; 31 GBq/mol。在这些13 F-放射性配体的生物分布研究中<18>，未观察到放射性的特异性蓄积，并且在研究的所有组织中均未发现1- [1-（2-噻吩基）-2-羟基-甲基环己基]哌啶（顺式-HPTC）的阻断作用，明确表明放射性是由于非选择性结合而分布的。在体外结合实验中也显示这些配体对NMDA受体的低亲和力。总之，新的配体不适合作为NMDA受体PET研究的体内放射性配体。因此，有必要使用亲水性更强的分子作为先导化合物，以开发有用的体内NMDA受体放射性配体。

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.