Synthesis and evaluation of an F-18-labeled dopa prodrug as a PET tracer for studying brain dopamine metabolism
Synthesis and evaluation of an F-18-labeled dopa prodrug as a PET tracer for studying brain dopamine metabolism
复制标题
DOI：
10.1016/0969-8051(95)02083-7
复制
发表时间：
1996-04-01
影响因子：
3.1
通讯作者：
Senda, M
中科院分区：
文献类型：
--
作者：
Ishiwata, K;Shinoda, M;Senda, M
在通过 PET 使用 6-[F-18]氟-L-多巴 (6-[F-18]FDOPA) 进行突触前多巴胺代谢的定量研究中，由于化合物对外周代谢的敏感性，需要在血浆中进行代谢分析以确定精确的输入函数。在本研究中，我们制备了 6-[F-18]氟-O-新戊酰-L-多巴 (6-[F-18]FPDOPA) 作为 6-[F-18]FDOPA 的前药，并评估了其作为小鼠 PET 示踪剂的潜力。如果6-[F-18]FPDOPA在外周稳定并在脑组织中水解为6-[F-18]FDDOPA，则将克服6-[F-18]FDOPA的缺点。与6-[F-18]FDDOPA相比，6-[F-18]FPDOPA的初始脑摄取量较低；然而，后者的摄取变得可比，并且纹状体与其他参考区域的摄取比率更大。给小鼠服用芳香氨基酸脱羧酶和儿茶酚-O-甲基转移酶抑制剂的药物大大增强了纹状体对这两种化合物的摄取。 L-苯丙氨酸负载导致大脑对化合物的摄取减少，表明中性氨基酸转运蛋白可通过血脑屏障转运。 HPLC分析显示纹状体中存在6-[F-18]FPDOPA、6-[F-18]FDOPA和6-[F-18]氟多巴胺；然而，与[F-18]FDOPA一样，6-[F-18]氟-3-O-甲基-L-多巴是大脑和血浆中的主要代谢物。结果表明6-[F-18]FPDOPA具有作为6-[F-18]FDDOPA前药的特征；然而，该化合物在体内也容易发生代谢改变。
In the quantitative studies of presynaptic dopamine metabolism by PET with 6-[F-18]fluoro-L-dopa (6-[F-18]FDOPA), metabolic analysis in the plasma is required to determine the precise input function because of susceptibility of the compound to peripheral metabolism. In this study, we prepared 6-[F-18]fluoro-O-pivaloyl-L-dopa (6-[F-18]FPDOPA) as a prodrug of 6-[F-18]FDOPA, and evaluated its potential as a PET tracer in mice. If the 6-[F-18]FPDOPA is stable peripherally and is hydrolyzed to 6-[F-18]FDOPA in the brain tissues, disadvantage of the 6-[F-18]FDOPA will be overcome. Compared with the 6-[F-18]FDOPA, the initial brain uptake of the 6-[F-18]FPDOPA was lower; however, the uptake in the latter become comparable, and the uptake ratios of striatum to other reference regions were larger. Medication of mice with inhibitors of aromatic amino acid decarboxylase and catechol-O-methyl transferase greatly enhanced the striatal uptake of the two compounds. The reduced brain uptake of the compounds by L-phenylalanine-loading suggested transport through the blood-brain barrier by the neutral amino acid transporter. HPLC analysis showed the presence of 6-[F-18]FPDOPA, 6-[F-18]FDOPA and 6-[F-18]fluorodopamine in the striatum; however, 6-[F-18]fluoro-3-O-methyl-L-dopa was a predominate metabolite in the brain and plasma as in the case of [F-18]FDOPA. Results suggested that 6-[F-18]FPDOPA had characteristics as a prodrug of 6-[F-18]FDOPA; however, the compound was also labile to metabolic alteration in vivo.