Ishiwata K, Shinoda M, Ishii S, Nozaki T, Senda M
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Japan.
Nucl Med Biol. 1996 Apr;23(3):295-301. doi: 10.1016/0969-8051(95)02083-7.
In the quantitative studies of presynaptic dopamine metabolism by PET with 6-[18F]fluoro-L-dopa (6-[18F]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-[18F]-fluoro-O-pivaloyl-L-dopa (6-[18F]FPDOPA) as a prodrug of 6-[18F]FDOPA, and evaluated its potential as a PET tracer in mice. If the 6-[18F]FPDOPA is stable peripherally and is hydrolyzed to 6-[18F]FDOPA in the brain tissues, disadvantage of the 6-[18F]FDOPA will be overcome. Compared with the 6-[18F]FDOPA, the initial brain uptake of the 6-[18F]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-[18F]FPDOPA, 6-[18F]FDOPA and 6-[18F]fluorodopamine in the striatum; however, 6-[18F]fluoro-3-O-methyl-L-dopa was a predominate metabolite in the brain and plasma as in the case of [18F]FDOPA. Results suggested that 6-[18F]FPDOPA had characteristics as a prodrug of 6-[18F]FDOPA; however, the compound was also labile to metabolic alteration in vivo.
在使用6-[18F]氟-L-多巴（6-[18F]FDOPA）通过正电子发射断层扫描（PET）对突触前多巴胺代谢进行定量研究时，由于该化合物易受外周代谢影响，因此需要对血浆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-[18F]氟-O-新戊酰基-L-多巴（6-[18F]FPDOPA）作为6-[18F]FDOPA的前体药物，并评估了其作为小鼠PET示踪剂的潜力。如果6-[18F]FPDOPA在外周稳定且在脑组织中水解为6-[18F]FDOPA，那么6-[18F]FDOPA的缺点将被克服。与6-[18F]FDOPA相比，6-[18F]FPDOPA的初始脑摄取较低；然而，后者的摄取量变得相当，并且纹状体与其他参考区域的摄取比率更大。用芳香族氨基酸脱羧酶和儿茶酚-O-甲基转移酶抑制剂对小鼠进行药物处理可大大增强这两种化合物在纹状体中的摄取。L-苯丙氨酸负荷导致化合物的脑摄取减少，这表明其通过中性氨基酸转运体穿过血脑屏障。高效液相色谱分析显示纹状体中存在6-[18F]FPDOPA、6-[18F]FDOPA和6-[18F]氟多巴胺；然而，与[18F]FDOPA的情况一样，6-[18F]氟-3-O-甲基-L-多巴是脑和血浆中的主要代谢产物。结果表明，6-[18F]FPDOPA具有作为6-[18F]FDOPA前体药物的特性；然而，该化合物在体内对代谢改变也不稳定。
