ポジトロン断層法によるヒト脳ドーパミン代謝測定へのF-18標識プロドラッグの応用

在体内评价了氟化多巴前体药物作为PET研究突触前多巴胺代谢示踪剂的潜力。6-[1F<18>]氟代-O-新戊酰基-L-多巴（6-[1F<18>]FPDOPA）是由4-O-新戊酰基-L-多巴与乙酰基[<18>1F]次氟酸盐直接酯化制得。在小鼠中，该化合物的脑摄取低于6-[13 <18>F]FDOPA ;然而，6-[13 F] FDOPA中纹状体与其他参照区域的摄取比率<18>大于6-[13 F] <18>FDOPA。芳香族氨基酸脱羧酶和儿茶酚-O-甲基转移酶的抑制剂增强了纹状体的选择性摄取; 6-[<18>^ F]FPDOPA的效果小于6-[^F] <18>FDOPA。通过L-苯丙氨酸负载降低了两种化合物的脑摄取，表明化合物通过血脑屏障的转运是由中性氨基酸转运系统介导的。经HPLC分析，在纹状体中发现了6-[^<18>F]FPDOPA、6-[^<18>F]FDOPA、6-[^<18>F]氟多巴胺等代谢产物，而<18>在其它脑区中未发现6-[^ F]氟多巴胺。结果表明6-[^<18>F]FPDOPA作为多巴前体药物的潜力，6-[^<18>F]FPDOPA经盐酸水解，然后用缓冲生理盐水作为洗脱液进行HPLC分离，得到无菌和无热原的6-[^<18>F]FDOPA注射液。该方法适用于人体PET研究的常规生产相比，错误报告的方法。在使用6-[1F]FDOPA的人体PET研究中<18>，已经开发了由PET获得的脑的代谢图像精确地叠加到由MRI获得的结构图像。本文对正常人纹状体多巴胺代谢进行了半定量测定。

The potential of a fluorinated dopa prodrug as a tracer for studying presynaptic dopamine metabolism by PET was evaluaed in vivo. 6-[^<18>F]fluoro-O-pivaloyl-L-dopa (6-[^<18>F]FPDOPA) was prepared by direct fluorination of 4-O-pIVALOYl-L-dopa with acetyl [^<18>F]hypofluorite. In mice, brain uptake of the compound was lower than that of 6-[^<18>F]FDOPA ; however, the uptake ratios of striatum-to-other reference regions was larger in the 6-[^<18>F]FPDOPA than in the 6-[^<18>F]fdopa. Inhibitors of aromatic amino acid decarboxylase and catechol-O-methyl transferase enhanced selective uptake by the striatum ; the effect was smaller for 6-[^<18>F]FPDOPA than for 6-[^<18>F]FDOPA.reduced brain uptake of both compounds by L-phenylalanine-loading suggested that transport of the compounds across the blood-brain barrier was mediated by the neutral amino acid transoport system. BY HPLC analysis, 6-[^<18>F]FPDOPA, 6-[^<18>F]FDOPA, 6-[^<18>F]fluorodopamine and other metabolies were found in the striatum, although 6-[^<18>F]fluorodopamine was not found in other brain regions. The results show the potential of 6-[^<18>F]FPDOPA as a dopa prodrug.The HCl-hydrysis of 6-[^<18>F]FPDOPA followed by HPLC separation using the buffered physiological saline as an eluting solution, gave a steril and apyrogenic 6-[^<18>F]FDOPA injection. The method was suitable for routine production in human PET studies as compared to the methods reported prevously. In human PET studies using 6-[^<18>F]FDOPA, the metabolic images of the brain obtained by PET were superimposed precicely to the structual images obatined by MRI, has been developed. Semi-quantitative assesment of doamine metabolism in the striatum has been performed in normal subjects.