Behavior of fluorinated analogs of L-(3,4-dihydroxyphenyl)alanine and L-threo-(3,4-dihydroxyphenyl)serine as substrates for Dopa decarboxylase

We have determined the kinetic parameters for Dopa decarboxylase (DDC) of three ring-fluorinated analogs of 3, 4-dihydr-oxyphenylalanine (Dopa). The rank order of catalytic e0ciency of decarboxylation (kcat/Km)is Dopa > 6-F-Dopa > 2-F-Dopa > 5-F-Dopa. This rank is consistent with previous in vivo and in vitro studies which indicate that of the fluorinated analogs 6-F-Dopa has pharmacokinetics that are most suited for positron emission tomographic (PET) evaluation of dopamine function. The effectiveness of PET as a diagnostic tool the convenient half-life of 18F (110 min) and the favorable pharmacokinetics of 6-[18F]FDOPA have combined to make this an extremely valuable reagent to study dopaminergic activity. The reactions of the related fluorinated DOPS analogs show that while 6-F-threo-3, 4-(dihydroxyphenyl)serine (DOPS) is decarboxylated at approximately the same rate as the non-fluorinated substrate 2-F-threo-DOPS is not converted into the corresponding amine. In both cases a Pictet-Spengler condensation with the pyridoxal 5′-phosphate (PLP) cofactor occurs to produce tetrahydroisoquinolines. Condensation of fluorinated catecholamines and catechol amino acids with endogenous aldehydes will be investigated as an approach to study possible mechanisms of L-Dopa-linked neurotoxicity. Published by Elsevier Science (USA).