Simultaneous PET imaging of rCBF and dopamine release

描述（由申请人提供）： 多巴胺能系统中的功能障碍涉及多种流行的和使人衰弱的病理学，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，该方法可用于更好地了解人类大脑系统水平的多巴胺能神经调节。这些研究将寻求细胞外多巴胺测量值的变化与大脑活动对刺激、任务或药物的反应之间的关联。由于扫描之间个体内的变化，同时成像多巴胺释放和局部脑血流（rCBF）的变化是有价值的。因此，这种双示踪剂方法涉及一种新的方案，用于在存在长寿命神经化学示踪剂[11 C]雷氯必利（t1/2 = 20 min）的情况下递送短寿命血流示踪剂[17 F]氟甲烷（t1/2 = 65 s）。使用这种技术的人类研究将揭示疾病的正常功能和机制，该技术可能具有诊断应用。 该项目包括对大鼠和恒河猴的初步研究沿着对人类研究的模拟。具体目标是：（1）基于大鼠探索性研究开发示踪剂递送方案和分析工具;（2）优化猴研究的递送方案;（3）研究猴对苯丙胺激发的神经调节反应，将同时观察到的纹状体多巴胺释放变化与不同脑区rCBF变化相关联;以及（4）基于模拟优化用于人体研究的递送方案。

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.