Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Nucl Med Biol. 2010 Jan;37(1):3-8. doi: 10.1016/j.nucmedbio.2009.08.013. Epub 2009 Oct 3.
The sensitivity of the in vivo binding of [(11)C]dihydrotetrabenazine ([(11)C]DTBZ) and [(11)C]methylphenidate ([(11)C]MPH) to their respective targets - vesicular monoamine transporter type 2 (VMAT2) and neuronal membrane dopamine transporter - after alterations in endogenous levels of dopamine was examined in the rat brain.
In vivo binding of [(11)C]DTBZ and [(11)C]MPH was determined using a bolus+infusion protocol. The in vitro number of VMAT2 binding sites was determined by autoradiography.
Repeated dosing with alpha-methyl-p-tyrosine (AMPT) at doses that significantly (-75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [(11)C]DTBZ binding to VMAT2 in the striatum. The increase in binding could be completely reversed via treatment with L-DOPA/benserazide to restore dopamine levels. There were no changes in the total number of VMAT2 binding sites, as measured using in vitro autoradiography. No changes were observed for in vivo [(11)C]MPH binding to the dopamine transporter in the striatum following AMPT pretreatment.
These results indicate that large reductions in dopamine concentrations in the rat brain can produce modest but significant changes in the binding of radioligands to VMAT2, which can be reversed by replenishment of dopamine using exogenous L-DOPA.
本研究旨在探讨大鼠脑内多巴胺内源性水平改变后，[(11)C]二氢四苯并嗪([(11)C]DTBZ)和[(11)C]哌醋甲酯([(11)C]MPH)与其各自靶标——囊泡单胺转运体 2（VMAT2）和神经元膜多巴胺转运体的体内结合的敏感性变化。
采用“bolus+infusion”方案，通过正电子发射断层扫描（PET）测定 [(11)C]DTBZ 和 [(11)C]MPH 的体内结合情况。通过放射自显影术测定 VMAT2 结合位点的体外数量。
重复给予α-甲基-对-酪氨酸（AMPT），剂量足以显著降低（-75%）脑内多巴胺水平，导致纹状体中 VMAT2 的体内 [(11)C]DTBZ 结合增加（+36%）。通过给予 L-DOPA/苯丙胺以恢复多巴胺水平，可完全逆转结合的增加。使用体外放射自显影术测量，VMAT2 结合位点的总数没有变化。在 AMPT 预处理后，纹状体中多巴胺转运体的体内 [(11)C]MPH 结合没有变化。
这些结果表明，大鼠脑内多巴胺浓度的大幅降低可导致放射性配体与 VMAT2 结合发生适度但显著的变化，通过外源性 L-DOPA 补充多巴胺可逆转这种变化。
