Vesicular Monoamine Transporter 2 Imaging in Cocaine Abuse

描述(申请人提供)：之前使用PET和SPECT内源性竞争结合技术的研究表明，与健康对照组相比，慢性可卡因使用者在急性苯丙胺挑战后释放的多巴胺较少。慢性可卡因使用者DA传递减少的一个可能解释是长期持续接触可卡因导致DA神经末梢丢失。以往研究DA终末的PET研究主要集中在血浆多巴胺转运体(DAT)和DA合成酶，如DOPA-脱羧酶。不幸的是，使用这些标记物进行的尸检和成像研究产生了不一致的结果，因为它们极易受到长期使用可卡因引起的多巴胺浓度波动的影响。与这些标记物相反，囊泡性单胺转运体2(VMAT2)标记物，如放射性标记(+)-二氢四苯并(DTBZ)，已被证明不容易被影响单胺类神经传递的药物调节。[11C]DTBZ首先被放射性标记，并被基尔伯恩和他的同事报告为PET放射性示踪剂，它与VMAT2结合，VMAT2仅位于突触前囊泡膜中。据报道，[11C]DTBZ与纹状体中的PET的体内结合在很大程度上(95%)代表了多巴胺能神经末梢中的储存囊。基于这些数据，我们建议使用[11C]DTBZ作为探针来测量可卡因依赖者DA终末的可用性。这些初步研究的结果将进一步加深我们对慢性可卡因滥用导致DA传递缺陷的机制的理解，并可能导致新的治疗方法。公共卫生相关性：在这项应用中，我们建议在PET实验中评估可卡因依赖者和与[11C]-(+)-DTBZ匹配的健康对照(HC)中VMAT2的体内状态

DESCRIPTION (provided by applicant): Previous studies using PET and SPECT endogenous competition binding techniques have shown that chronic cocaine users relative to healthy controls release less dopamine following an acute amphetamine challenge. A likely explanation for a decrease in DA transmission in chronic cocaine users is a loss of DA nerve terminals caused by chronic and persistent exposure to cocaine. Previous PET investigations to study DA terminals have focused primarily on the plasmalemmal dopamine transporter (DAT) and DA synthesis enzymes such as DOPA-decarboxylase. Unfortunately postmortem and imaging studies conducted with these markers have yielded inconsistent results for they are extremely vulnerable to fluctuations in dopamine concentrations caused by chronic cocaine use. In contrast to these markers the vesicular monoamine transporter type 2 (VMAT2) markers such as radiolabeled (+)- dihydrotetrabenazine (DTBZ) have been shown to not be readily regulated by drugs that can affect monoamine neurotransmission. [11C]DTBZ, first radiolabeled and reported as a PET radiotracer by Kilbourn and colleagues binds to the VMAT2, which is located exclusively in the pre-synaptic vesicular membranes. The in vivo binding of [11C]DTBZ as measured with PET in the striatum has been reported to largely (>95%) represent storage vesicles in the dopaminergic nerve terminals. Based on these data we propose to use [11C]DTBZ as a probe to measure the availability of DA terminals in cocaine dependent human subjects. The results of these preliminary studies will further our understanding of the mechanism by which chronic cocaine abuse leads to DA transmission deficits and potentially lead to novel treatments. PUBLIC HEALTH RELEVANCE: In this application, we propose to evaluate in vivo status of VMAT2 in cocaine dependent subjects and matched healthy controls (HC) with [11C]-(+)-DTBZ in PET experiments