Carbon-11-d-threo-methylphenidate binding to dopamine transporter in baboon brain

The more active d-enantiomer of methylphenidate (dl-threo-methyl-2-phenyl-2-(2-piperidyl)acetate, Ritalin) was labeled with 11C(t1/2:20.4 min) to characterize its binding, examine its specificity for the dopamine transporter and evaluate it as a radio-tracer for the presynaptic dopaminergic neuron.

PET studies were carried out in the baboon. The pharmacokinetics of [11C]dl-threo-methylphenidate, [11C]l-threo-MP and with its racemate ([11C]dl-threo-methylphenidate, [11C]MP). Nonradioactive methylphenidate was used to assess the reversibility and saturability of the binding. GBR 12909, 3 beta-(4-iodophenyl)tropane-2-carboxylic acid methyl ester (beta-CIT), tomoxetine and citalopram were used to assess the binding specificity.

The ratio between radioactivity in the striatum and that in the cerebellum (ST/CB) after injection of [11C]d-threo-MP was higher than that for [11C]MP and [11C]l-threo-MP (3.3 for d-, 2.2 for racemic and 1.1 for l- in the same baboon). Most of the striatal binding of [11C]d-threo-MP was displaceable by injection of nonradioactive MP. Pretreatment with nonradioactive MP (0.5 mg/kg), GBR12909 (1.5 mg/kg) and RTI-55 (0.3 mg/kg) markedly reduced striatal but not cerebellar uptake of [11C]d-threo-MP. In all cases, the ST/CB after pretreatment was reduced by about 60% compared to 43% for [11C]MP. The ratios of distribution volumes at steady-state for the ST/CB for the three separate studies in the same baboon were reduced by about 50%, as compared with 37% for [11C]MP. In contrast, pretreatment with tomoxetine (3.0 mg/kg) or citalopram (2.0 mg/kg) did not change [11C]d-threo-MP kinetics; the ST/CB after pretreatment was similar to that for the control.

These results demonstrate the saturable, reversible and specific binding of [11C]d-threo-MP to the dopamine transporter on the baboon brain, suggesting that [11C]d-threo-MP will be a useful PET tracer for the presynaptic dopaminergic neuron in living human brain.