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.

抽象的 非侵入性神经成像已成为研究人脑功能研究的主要工具 健康与疾病。当前，PET代表了我们唯一的非侵入性探测工具 神经递质释放，大多数此类研究都集中在多巴胺系统上。 尽管对大脑的某些神经化学过程具有精致的分子特异性 激活，关于宠物信号来源的问题和推论的准确性 基于放射性示例的位移。为了解决这些问题，我们建议 机械研究和激动剂放射性示踪剂（[11C] phno）的更好表征 承诺对多巴胺释放的敏感性更好。为了解释信号的来源，我们最近 工作的重点是将PET与并发fMRI结合在一起，以补充 通过fMRI的受体占用率的PET测量提供的神经化学签名 描述该占用的功能后果的读数。为了设定舞台 提取宠物占用率的微妙变化，我们描述 应该减少系统偏见的模型。为了了解fMRI信号的关系 为了改变占用率，我们开发了简单的单一和多受体模型 多巴胺诱导的fMRI信号。根据以前间接建议的宠物工作 对受体激动剂和拮抗剂的不同反应可能表明神经受体 贩运，我们已经确定了动力学家与拮抗剂的不同PET/FMRI关系。在 拟议的研究，我们将与多巴胺结合使用小鼠敲除模型 微透析以更直接地检验有关受体运输如何影响PET和的假设 FMRI信号，我们将对非人类灵长类动物（NHP）进行临床扫描仪的研究 使用两种不同的放射性示例证明急性和慢性多巴胺刺激的影响 （[11c] Phno和[11c] raclopride）。我们将利用NHP中的单侧深脑刺激（DB） 产生单方面，焦点和可滴定的多巴胺释放模型，可以通过 同时进行fMRI，并用于比较每个放射性示踪剂对多巴胺的敏感性 发布。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11C] PHNO和[11C] raclopride和 表征空间响应与同时获得的fMRI。拟议的研究将 有助于提高我们对内源性神经递质释放宠物测量的理解 并可能导致对行为调制的多巴胺释放的更强大的测量 人类主题。