Carbon-11-d-threo-methylphenidate binding to dopamine transporter in baboon brain.
Carbon-11-d-threo-methylphenidate binding to dopamine transporter in baboon brain.
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发表时间：
1995-12
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通讯作者：
Y. Ding;J. Fowler;N. Volkow;J. Logan;S. Gatley;Y. Sugano
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作者：
Y. Ding;J. Fowler;N. Volkow;J. Logan;S. Gatley;Y. Sugano
未标记用11 C（t1/2：20.4 min）标记哌甲酯（dl-苏型-甲基-2-苯基-2-（2-哌啶基）乙酸酯，利他林）的活性更高的d-对映体，以表征其结合，检测其对多巴胺转运蛋白的特异性，并评价其作为突触前多巴胺能神经元的放射性示踪剂。方法在狒狒中进行PET研究。[11 C] dl-苏型-哌甲酯、[11 C] l-苏型-MP及其外消旋体（[11 C] dl-苏型-哌甲酯，[11 C]MP）的药代动力学。非放射性哌甲酯用于评估结合的可逆性和饱和性。使用GBR 12909、3 β-（4-碘苯基）托烷-2-羧酸甲酯（β-CIT）、托莫西汀和西酞普兰评估结合特异性。结果注射[11 C] d-苏型MP后，纹状体与小脑的放射性比值（ST/CB）明显高于[11 C]MP和[11 C] l-苏型MP（d-为3.3，消旋为2.2，l-为1.1）。大多数纹状体结合的[11 C]d-threo-MP可通过注射非放射性MP进行置换。用非放射性MP（0.5 mg/kg）、GBR 12909（1.5 mg/kg）和RTI-55（0.3 mg/kg）预处理显著减少纹状体而不是小脑对[11 C]d-threo-MP的摄取。在所有情况下，与[11 C]MP的43%相比，预处理后的ST/CB降低了约60%。在同一狒狒中进行的三项独立研究中，ST/CB稳态分布容积比降低约50%，而[11 C]MP为37%。相比之下，预先给予托莫西汀（3.0 mg/kg）或西酞普兰（2.0 mg/kg）并没有改变[11 C] d-苏型-MP动力学;预处理后的ST/CB与对照组相似。结论[11 C]d-threo-MP与狒狒脑多巴胺转运体的结合是可饱和的、可逆的和特异的，提示[11 C]d-threo-MP有望成为活体人脑多巴胺能神经元突触前的PET示踪剂。
UNLABELLED 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. METHODS 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. RESULTS 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. CONCLUSION 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.