PET Imaging of Serotonin Transmission in MDMA Users

描述（由申请人提供）：娱乐性药物（+/-）3，4-亚甲二氧基甲基苯丙胺（MDMA;"迷魂药"）的使用在美国和世界范围内不断增加。MDMA是一种有效的5-羟色胺（5-HT）兴奋剂。在动物中，暴露于MDMA与5-HT神经元的长期损伤有关。由于用于人体的剂量与已知可导致动物5-羟色胺神经元损伤的剂量重叠，人们非常担心娱乐性使用MDMA可能会导致长期5-羟色胺神经毒性。5-HT神经毒性可能导致神经认知障碍、行为控制改变以及易患情绪和焦虑症。 核医学的最新进展使得能够直接定量活体人脑中的5-HT相关蛋白。5-HT转运体（SERT）仅位于5-HT轴突终末。最近用PET和SPECT进行的SERT成像研究报告的数据表明，重度MDMA使用者的SERT密度降低，这一发现在女性使用者中可能比男性更明显。此外，突触后5-HT 2A受体的初步成像研究报告了MDMA使用者中该受体的密度增加，这一发现可能反映了继发于5-HT耗竭的上调。然而，这些研究是用具有低选择性或低信噪比的第一代PET和SPECT放射性示踪剂进行的。由于这些技术上的限制，它仍然是不确定的，是否，以及在何种程度上，5-HT系统是在娱乐MDMA用户的损害。 鉴于这个问题对公共卫生的重要性日益增加，我们建议利用放射性配体开发的最新进展来研究这个问题。[11 C] DASB和[11 C] MDL100907是分别用于SERT和5-HT 2A受体成像的新型高选择性放射性示踪剂。与第一代5-HT放射性配体相比，这些放射性示踪剂在图像质量上有很大改善，并能够可靠地定量其在活体大脑中的靶蛋白。 30例重度MDMA使用者（15例男性和15例女性）和30例匹配的MDMA-na？在18天的监测戒断期后，对5名对照进行[11 C] DASB和[11 C] MDL 100907 PET扫描。待检验的假设是，SERT和5-HT 2A受体密度分别减少和增加，在MDMA用户与对照组相比，这些变化在女性中比男性更明显，并与以前的MDMA暴露量有关。

DESCRIPTION (provided by applicant): The use of the recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') is increasing in the US and the world. MDMA is a potent serotonin (5-HT) releaser. In animals, exposure to MDMA is associated with long-lasting damage to 5-HT neurons. As doses used in humans overlap with doses known to produce lesions of 5-HT neurons in animals, there is a very serious concern that long-term 5-HT neurotoxicity might result from the recreational use of MDMA. 5-HT neurotoxicity might lead to neurocognitive impairment, altered behavioral control, and vulnerability to mood and anxiety disorders. Recent progress in nuclear medicine has enabled direct quantification of 5-HT related proteins in the living human brain. The 5-HT transporter (SERT) is located exclusively on 5-HT axonal terminals. Recent imaging studies of the SERT with PET and SPECT have reported data suggesting that SERT density is decreased in heavy MDMA users, a finding that may be more pronounced in female users than in males. In addition, preliminary imaging studies of the post-synaptic 5-HT2A receptor have reported an increased density of this receptor in MDMA users, a finding that might reflect an upregulation secondary to 5-HT depletion. However, these investigations were carried out with first generation PET and SPECT radiotracers which have low selectivity or low signal to noise ratios. Because of these technical limitations it is still uncertain whether, and to what extend, the 5-HT system is lesioned in recreational MDMA users. Given the growing importance of this question for public health, we propose to capitalize on recent progress in radioligand development to examine this question. [11C]DASB and [11C]MDL100907 are new and highly selective radiotracers for imaging the SERT and 5-HT2A receptor, respectively. These radiotracers provide great improvement in image quality over the first generation of 5-HT radioligands, and enable reliable quantification of their target proteins in the living brain. Thirty (30) heavy MDMA users (15 males and 15 females) and 30 matched MDMA-na?ve controls will undergo PET scans with [11C]DASB and [11C]MDL 100907 following an 18 day period of monitored abstinence. The hypotheses to be tested are that SERT and 5-HT2A receptor densities are decreased and increased, respectively, in MDMA users compared to controls, and that these alterations are more pronounced in females compared to males and related to magnitude of previous MDMA exposure.