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

在体内评价了含氟多巴前药作为PET研究突触前多巴胺代谢的示踪剂的潜力。用乙酰次氟酸盐直接氟化4-O-对羟基-L-多巴，合成了6-[1，2-二苯基]-2，4-二氢-2，4-二氢-2，4-二氢呋喃-L-多巴(6-FPDOPA)。在小鼠中，大脑对该化合物的摄取低于6-FDOPA；然而，6-[18&gt；18&gt；F]FDOPA纹状体与其他参照区的摄取比率高于6-[18&gt；F]FDOPA。芳香族氨基酸脱羧酶和儿茶酚-O-甲基转移酶抑制剂可增强纹状体选择性摄取，6-FPDOPA的作用小于6-FDOPA。L-苯丙氨酸负荷减少了这两种化合物的脑摄取，表明化合物的跨血脑屏障转运是由中性氨基酸转运系统介导的。经高效液相色谱分析，纹状体有6-FPDOPA、6-FDOPA、6-[18&gt；F]氟多胺等代谢产物，而其他脑区未检测到6-[18&gt；F]氟多胺。结果表明，6-FPDOPA具有作为多巴前体药物的潜力，6-[18&GT；F]FPDOPA经盐酸水解后，以缓冲生理盐水为洗脱液进行高效液相色谱分离，得到一种无菌无热致6-[18；F]FDOPA注射剂。与以往报道的方法相比，该方法适用于人体PET研究中的常规生产。在使用6-FDOPA的人体PET研究中，由PET获得的大脑代谢图像被精确地叠加到MRI获得的结构图像上。对正常受试者进行了纹状体多巴胺代谢的半定量测定。

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.