Altered behavioural and neurochemical profile of L-DOPA following deuterium substitutions in the molecule.

In Parkinson's disease patients, a prolonged half-life of dopamine formed from L-DOPA may reduce the risk of developing L-DOPA-induced side-effects. Deuterium substitutions in the L-DOPA molecule are expected to yield dopamine with an altered half-life because C-D bonds are more stable than C-H bonds. Therefore we tested, in the rat, the neurochemical and behavioral effects of different types of L-DOPA with deuterium substitutions at the alpha-carbon and/or the beta-carbon. By means of microdialysis, we found that L-DOPA with 3 deuterium substitutions (D3-L-DOPA) enhanced dopamine output in the striatum more effectively than L-DOPA and all the other deuterium variants. Moreover, D3-L-DOPA produced a more pronounced stimulation of locomotor activity in reserpinized rats compared to conventional L-DOPA. In contrast beta,beta-D2-L-DOPA was less effective than L-DOPA in raising striatal dopamine levels and was ineffective at restoring locomotor activity in reserpinized rats. These results demonstrate that the introduction of deuterium at different positions in the L-DOPA molecule dramatically changes its behavioral and neurochemical profile and suggest that L-DOPA treatment of Parkinson's disease may be improved in this way.