Dopamine-induced PET occupancy explored by PET/fMRI

通过 PET/fMRI 探索多巴胺诱导的 PET 占据

• 批准号: 9926322
• 负责人: JOSEPH B MANDEVILLE
• 金额: $ 65.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926322
• 关键词: Acute; Address; Affinity; Agonist; Amphetamines; Animal Model; Arrestins; Basal Ganglia; Behavior; Behavioral; Behavioral Model; Binding; Biological Markers; Brain; Chronic; Clinical; Comparative Study; Complement; Deep Brain Stimulation; Detection; Disease; Dissociation; Dopamine; Drug abuse; Equilibrium; Evaluation; Functional Magnetic Resonance Imaging; Generations; Health; Human; Human Volunteers; Kinetics; Knock-out; Knockout Mice; Lead; Ligand Binding; Ligands; Light; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mental Depression; Mental disorders; Methodology; Methods; Microdialysis; Mission; Modeling; Molecular; Monitor; Movement Disorders; Multimodal Imaging; Nucleus Accumbens; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Play; Positron-Emission Tomography; Primates; Process; Publishing; Raclopride; Rewards; Role; Schizophrenia; Sensory Receptors; Signal Transduction; Source; Specificity; System; Systematic Bias; Testing; Tissues; Tracer; United States National Institutes of Health; Validation; Ventral Tegmental Area; Water; Wild Type Mouse; Work; base; behavior measurement; desensitization; dopamine system; financial incentive; human subject; improved; indexing; kinetic model; mathematical model; microstimulation; molecular imaging; mouse model; neurochemistry; neuroimaging; neurotransmitter release; nonhuman primate; novel; novel marker; radioligand; radiotracer; receptor; receptor binding; receptor internalization; response; tool; trafficking

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.

摘要 非侵入性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，与大多数这样的研究集中在多巴胺系统。 尽管大脑中的某些神经化学过程具有精细的分子特异性， 激活，问题仍然是关于PET信号的来源和推断的准确性 基于放射性示踪剂的位移。为了解决这些问题，我们建议 对一种激动剂放射性示踪剂（[11 C]PHNO）的机制研究和更好的表征， 保证对多巴胺释放更敏感为了帮助解释信号的来源，我们最近的 工作集中在将PET与同时进行的fMRI结合起来，以补充 通过PET测量fMRI受体占有率提供的神经化学特征 描述该占用的功能后果的读数。为了给 提取PET占用的细微变化，我们描述了一种改进的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成像信号之间的关系， 对于占有率的变化，我们已经开发了简单的单和多受体模型， 多巴胺诱导的fMRI信号。根据先前的PET工作，间接地表明 对受体激动剂和拮抗剂的不同反应可能指示神经受体 通过分析药物的运输，我们已经确定了激动剂与拮抗剂的不同PET/fMRI关系。在 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运输如何影响PET的假设， fMRI信号，我们将在临床扫描仪上对非人类灵长类动物（NHP）进行研究， 使用两种不同的放射性示踪剂证明急性和慢性多巴胺刺激的效果 （[11 C]PHNO和[11 C]雷氯必利）。我们将在NHP中使用单侧脑深部电刺激（DBS）， 产生单侧、局灶性和可滴定的多巴胺释放模型，可通过以下方法进行验证： 同时进行功能磁共振成像，并用于比较每种放射性示踪剂对多巴胺的敏感性 release.作为翻译的补充，我们将在健康的人类志愿者中进行研究， 使用[11 C]PHNO和[11 C]雷氯必利测试行为调节多巴胺的大小， 表征空间响应与同时获得的功能磁共振成像。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 并可能导致更强大的测量行为调制多巴胺释放 人类实验对象