Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and l-threo-methylphenidate in the human and baboon brain

A bstract  Methylphenidate (Ritalin) is the most commonly prescribed psychoactive medication for children in the US where it is used for the treatment of attention deficit hyperactivity disorder. Methylphenidate is marketed as a racemic mixture of the d-threo and l-threo enantiomers. It is believed that the d enantiomer is responsible for the therapeutic effect of methylphenidate. In this study we labeled the individual enantiomers with carbon-11 and compared their binding and pharmacokinetics in the human and baboon brain. Microdialysis studies in the rat were performed to compare their potency in elevating striatal dopamine concentration. Positron emission tomographic (PET) studies with ¹¹C]d-threo-methylphenidate (¹¹C]d-threo-MP) demonstrated highest regional uptake in basal ganglia. In contrast, ¹¹C]l-threo-methylphenidate (¹¹C]l-threo-MP) displayed similar uptakes in all brain regions. The ratios of distribution volumes at the steady-state for the basal ganglia to cerebellum (DV_BG/DV_CB) ranged from 2.2 to 3.3 for ¹¹C]d-threo-MP in baboon and human, and only 1.1 for ¹¹C]l-threo-MP. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) markedly reduced the striatal but not the cerebellar uptake of ¹¹C]d-threo-MP, whereas there was no effect on DV_BG/DV_CB for ¹¹C]l-threo-MP. In the rat, d-threo-MP increased extracellular dopamine concentration by 650% whereas l-threo-MP did not affect dopamine levels. These results indicate that pharmacological specificity of MP resides entirely in the d-threo isomer and directly show that binding of the l-isomer in human brain is mostly non-specific. Received: 18 September 1996 / Final version: 18 November 1996