Synthesis and evaluation of an F-18-labeled dopa prodrug as a PET tracer for studying brain dopamine metabolism

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.