Dopamine-induced PET occupancy explored by PET/fMRI

摘要 无创神经成像已成为研究人类大脑功能的主要工具 健康和疾病。目前，PET是我们唯一的非侵入性探测工具 神经递质的释放，大多数此类研究都集中在多巴胺系统上。 尽管对大脑潜在的一些神经化学过程具有精致的分子特异性 激活后，关于PET信号的来源和推断的准确性的问题仍然存在 基于放射性示踪剂的位移。为了解决这些问题，我们建议 一种激动剂放射性示踪剂([11C]PHNO)的机理研究和更好的表征 承诺对多巴胺释放更敏感。为了帮助解释信号的来源，我们最近 工作的重点是将PET与并发功能磁共振相结合，以补充 功能磁共振成像PET测量受体占位率提供的神经化学特征 描述该占用的功能后果的读数。为了为…做好准备 提取PET占有率的细微变化，我们已经描述了一种改进的PET示踪剂-动力学 应该减少系统性偏差的模型。为了了解功能磁共振信号之间的关系 对于入住率的变化，我们开发了简单的单受体和多受体模型 多巴胺诱导的fMRI信号。根据之前的PET工作，间接地表明 对可能代表神经受体的受体激动剂和拮抗剂的不同反应 对于药物贩运，我们已经确定了激动剂和拮抗剂之间不同的PET/fMRI关系。在……里面 在拟议的研究中，我们将利用小鼠基因敲除模型结合多巴胺 微透析以更直接地测试关于受体转运如何影响PET和 FMRI信号，我们将在临床扫描仪上对非人类灵长类(NHP)进行研究，以 用两种不同的放射性示踪剂演示急性和慢性多巴胺刺激的效果 ([11C]PHNO和[11C]拉氯普利)。我们将在NHP中使用单侧脑深部刺激(DBS)来 建立单侧、焦点和可滴定的多巴胺释放模型，可通过以下方式进行验证 同步功能磁共振成像，用于比较每个放射性示踪剂对多巴胺的敏感性 放手。作为翻译补充，我们将在健康的人类志愿者中进行研究，以 用11C]PHNO和[11C]RACLOPBILE测试行为调节多巴胺的大小 描述空间反应与同时获得的fMRI的特征。拟议的研究将 有助于提高我们对PET测量内源性神经递质释放的理解 并可能导致对行为调节性多巴胺释放的更有力的测量 人类受试者。

Abstract Non-invasive neuroimaging has become a dominant tool in studies of human brain function in health and disease. Currently, PET represents our only tool for non-invasively probing neurotransmitter release, with the majority of such studies focusing on the dopamine system. Despite the exquisite molecular specificity to some of the neurochemical processes underlying brain activation, questions remain about the source of the PET signal and the accuracy of inferences based upon displacement of radiotracer. In order to address these issues, we propose mechanistic studies and better characterization of an agonist radiotracer ([11C]PHNO) that promises better sensitivity to dopamine release. To help interpret the source of signal, our recent work has focused upon combining PET with concurrent fMRI in order to supplement the neurochemical signature provided by PET measurements of receptor occupancy with an fMRI readout describing the functional consequences of that occupancy. In order to set the stage for extracting subtle changes in PET occupancy, we have described a refined PET tracer-kinetic model that should reduce systematic bias. In order to understand the relationship of fMRI signals to changes in occupancy, we have developed simple single and multi-receptor models of dopamine-induced fMRI signal. In accordance with prior PET work that indirectly suggested divergent responses to receptor agonists and antagonists that might be indicative of neuroreceptor trafficking, we have identified different PET/fMRI relationships for agonists versus antagonists. In the proposed studies, we will utilize a mouse knock-out model in conjunction with dopamine microdialysis to more directly test hypotheses about how receptor trafficking influences PET and fMRI signals, and we will perform studies in non-human primates (NHP) on clinical scanners to demonstrate effects of acute and chronic dopamine stimulation using two different radiotracers ([11C]PHNO and [11C]raclopride). We will utilize unilateral deep brain stimulation (DBS) in NHP to produce a unilateral, focal, and titratable model of dopamine release that can be validated by simultaneous fMRI and used to compare the sensitivity of each radiotracer to dopamine release. As a translational complement, we will perform studies in healthy human volunteers to test the magnitude of behaviorally-modulated dopamine using 11C]PHNO and [11C]raclopride and characterize the spatial response versus simultaneously acquired fMRI. The proposed studies will help improve our understanding of PET measurements of endogenous neurotransmitter release and may lead to more robust measurements of behaviorally modulated dopamine release in human subjects.