Simultaneous PET imaging of rCBF and dopamine release

描述(由申请人提供)： 多巴胺能系统的故障与各种流行的和令人衰弱的病理有关，例如注意力缺陷障碍、帕金森氏症、成瘾和精神分裂症。该项目的长期目标是开发一种正电子发射断层扫描(PET)方法，该方法可用于在人脑系统水平上更好地了解多巴胺能神经调节。这样的研究将寻求将细胞外多巴胺的测量与大脑活动对刺激、任务或药物的反应的变化联系起来。由于个体在不同扫描之间的差异，同时成像多巴胺释放和局部脑血流量(RCBF)的变化是有价值的。因此，这种双重示踪方法包括了一种新的方案，用于在长寿神经化学示踪剂[11C]拉氯普利(T1/2=20分钟)的存在下，传递短期血流示踪剂[17F]氟甲烷(T1/2=65 S)。使用这项技术的人体研究将揭示疾病的正常功能和机制，这项技术可能会有诊断应用。 该项目包括对大鼠和恒河猴的初步研究，以及对人类研究的模拟。其具体目标是：(1)开发基于大鼠探索性研究的示踪剂释放方案和分析工具；(2)优化猴子研究的示踪剂释放方案；(3)研究猴子对苯丙胺刺激的神经调制反应，将纹状体多巴胺释放的变化与不同大脑区域rCBF的变化相关联；以及(4)基于模拟，优化用于人体研究的给药方案。

DESCRIPTION (provided by applicant): Malfunctions in the dopaminergic system are implicated in a variety of prevalent and debilitating pathologies, e.g. attention deficit disorders, Parkinson's, addiction, and schizophrenia. This project's long-term goal is the development of a positron emission tomography (PET) method that may be applied to better understand dopaminergic neuromodulation at the systems level in the human brain. Such studies would seek to correlate alterations in measures of extracellular dopamine and brain activity in response to stimuli, tasks, or drugs. Because of variation within an individual between scans, it is valuable to simultaneously image dopamine release and changes in regional cerebral blood flow (rCBF). Therefore, this dual tracer method involves a novel protocol for delivering a short lived blood flow tracer, [17F]fluoromethane (t1/2 = 65 s), in the presence of a long lived neurochemical tracer, [11C]raclopride (t1/2 = 20 min). Human studies using this technique would shed light on normal function and mechanisms of disease, and the technique could have diagnostic applications. This project consists of preliminary studies in rats and rhesus monkeys along with simulations of human studies. The specific aims are to (1) develop a tracer delivery protocol and analytical tools based on exploratory studies with rats; (2) optimize the delivery protocols for monkey studies; (3) study the neuromodulatory response to an amphetamine challenge in monkeys, correlating simultaneous observations of alterations in striatal dopamine release and variations in rCBF in various brain regions; and (4) optimize the delivery protocols for human studies based on simulations.