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Carbon-11-d-threo-Methylphenidate Binding to Dopamine Transporter in Baboon Brain

Brookhaven National Laboratory, Upton, New york
Department of Psychiatry, SUNY Stony Brook, Stony Brook, NY

Correspondence: For correspondence or reprints contact: Yu-shin Ding, PhD, Department of chemistry, Bldg. 555, Brookhaven National Laboratory, Upton, NY 11973.

ABSTRACT

The more active d-enantiomer of methylphenidate (dl-threo-methyl-2-phenyl-2-(2-piperidyl)acetate, Ritalin) was labeled with ¹¹c (t_1/2:20.4 min) to characterize its binding, examine its specificity for the dopamine transporter and evaluate it as a radiotracer for the presynaptic dopaminergic neuron. Methods: PET studies were cariied out in the baboon. The pharmacokinetics of ([¹¹c]d-threO-methylphenidate ([¹¹C]d-threo-MP) were measured and compared with [¹¹C]I-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, 3ß-(4-iodophenyl)tropane-2-carboxylic acid methyl ester (ß-CIT), tomoxetine and citalopram were used to assess the binding specificity. Results: The ratio between radioactivity in the striatum and that in the cerebellum (ST/CB) after injection of [¹¹C]d-thre-MP was higher than that for [¹¹C]MP and [¹¹C]I-threo-MP (3.3 for d-, 2.2 for racemic and 1.1 for I- 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/GB 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]w-threo-MP kinetics; the ST/GB after pretreatment was similar to that for the control. Conclusion: These results demonstrate the saturable, reversible and specific binding of [¹¹C]d-threo-MP to the dopamine transporter in the baboon brain, suggesting that [¹¹C]d-thre-MP will be a useful PET tracer for the presynaptic dopaminergic neuron in living human brain.

Key Words: carbon-11-d-threo methylphenidate • dopamine transporter • stereoselectivity • dopaminergic neuron

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