Pharmacokinetics and in vivo specificity of [LLC]dl‐threo‐methylphenidate for the presynaptic dopaminergic neuron

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Abstract
dl‐threo‐Methylphenidate (Ritalin) was labeled with carbon‐11 (t1/2:20.4 minutes) in order to measure its pharmacokinetics, to evaluate it as a radiotracer for the presynaptic dopaminergic neuron, and to examine its sensitivity to the loss of dopaminergic neurons. Positron emission tomographic (PET) studies were carried out in the baboon to determine specificity for the presynaptic dopaminergic neuron and in humans to assess sensitivity to neuronal loss. Studies with [llC]dl‐threo‐methylphenidate ([llC]MP) in baboon demonstrated high regional uptake in the striatum. Peak uptake (0.04%/cc) occurred at 5‐15 minutes post‐injection. The half‐time for clearance from peak uptake for [11C]MP was 60 minutes and the ratio between the radioactivity in the striatum and that in the cerebellum (ST/CB) ranged from 2.2 to 2.6 at 40 minutes. Repeated measures in the same baboon showed ≤8% variability in the ST/CB ratio. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) 30 minutes prior to [11C]MP injection markedly reduced the striatal but not the cerebellar uptake of [11C]MP, demonstrating the saturable and specific binding of [11C]MP to a site on the dopamine transporter in the brain. In both cases, the ratio of striatum to cerebellum (ST/CB) after pretreatment was reduced by about 43% The ratios of distribution volumes at the steady‐state for the striatum to cerebellum (ST/CB) for these two separate studies in the same baboon were reduced by 37 and 38%, respectively. In contrast, pretreatment with tomoxetine (1.5 mg/kg) or citalopram (2.0 mg/kg), inhibitors of the norepinephrine and serotonin transporter, respectively, did not produce a significant change in the kinetics of [11C]MP and the ST/CB after pretreatment was similar to that for control. In one patient with Parkinson's disease, the striatum to cerebellum ratio of [11C]MP was markedly lower than that of an elderly normal subject. These results demonstrate the saturable [11C]MP binding to the dopamine transporter in the baboon brain and that [11C]MP is sensitive to dopamine neuron degeneration in Parkinson's disease. © 1994 Wiley‐Liss, Inc This article is a US Government work and, as such, is in the public domain in the United States of America .

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