Toward functional molecular neuroimaging using vasoactive probes in human subjects

在人类受试者中使用血管活性探针进行功能性分子神经成像

• 批准号: 10253338
• 负责人: Alan Jasanoff
• 金额: $ 65.81万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-09 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10253338
• 关键词: Address; Aging; Animals; Antibodies; Architecture; Autopsy; Behavioral; Biotin; Blood - brain barrier anatomy; Brain; Bypass; Callithrix; Carrier Proteins; Chemicals; Clinical; Cognition; Contrast Media; Cultured Cells; Data; Detection; Diffuse; Disease; Dopamine; Drug usage; Engineering; Enzymes; Functional Magnetic Resonance Imaging; Glutamates; Goals; Health; Human; Injections; Laboratories; Magnetic Resonance Imaging; Magnetism; Maps; Measurement; Mediating; Methods; Modeling; Molecular; Molecular Probes; Monitor; Monkeys; Neurobiology; Neurosciences; Neurotransmitters; Optics; Outcome; Perception; Peripheral; Permeability; Positron-Emission Tomography; Primates; Process; Radioactive; Reagent; Resolution; Rodent; Role; Signal Transduction; Source; Specificity; Stimulus; Technology; Testing; Time; Ultrasonography; Validation; Variant; Work; base; blood oxygen level dependent; blood-brain barrier permeabilization; design; experience; experimental study; hemodynamics; human subject; imaging agent; imaging modality; imaging probe; in vitro testing; in vivo imaging; intravenous injection; molecular scale; monoamine; neural circuit; neurochemistry; neuroimaging; neurophysiology; non-invasive imaging; nonhuman primate; novel; overexpression; receptor; research clinical testing; response; sensor; small molecule; spatiotemporal; transcytosis; translation to humans

We propose to develop a probe technology for monitoring human brain function with molecular precision; in conjunction with magnetic resonance imaging (MRI) or other imaging modalities, the probes will provide a combination of sensitivity and resolution that could permit unprecedented noninvasive studies of dynamic neu- rophysiological processes in people. Our strategy is based on a fundamentally new type of chemical imaging probe designed to produce neuroimaging readouts by purposefully manipulating endogenous hemodynamic contrast in the brain—repurposing the blood oxygen level dependent (BOLD) effect that underlies conventional functional MRI (fMRI). This new “vasoprobe” concept offers three key advantages: First, by providing time-de- pendent sensitivity to dilute molecular species such as neurotransmitters, the probes can enable well-defined neurobiological phenomena to be mapped dynamically across the entire brain, dramatically surpassing existing nonspecific fMRI approaches. Second, because of the endogenous contrast source they influence, the probes are detectable on a variety of spatiotemporal scales by noninvasive imaging modalities complementary to fMRI, such as diffuse optical or ultrasound-based methods. Third, by circumventing limitations of established optical, magnetic, and radioactive probe designs, vasoprobes combine exquisite sensitivity approaching that of positron emission tomography (PET) with the resolution and versatility of MRI. In this project, we will build on our recent proof-of-concept work with vasoprobes to establish noninvasive brain-wide delivery strategies and to develop robust neurochemical sensors that function in primates. The technology we establish will address multiple goals in basic and applied neuroscience, and we expect it to yield molecular probes that will be appropriate for clinical evaluation in human subjects by the end of the project period. In Aim 1, we will create vasoprobe variants that can be delivered to the brain via intravenous injection and spontaneous permeation through the blood-brain barrier (BBB). We will form conjugates of vasoprobe-based sensors with “brain shuttle” antibodies that have previously been shown to enable brain import via receptor- mediated transcytosis. Demonstration of brain-permeable vasoprobes will establish a clinically viable path for facile, noninvasive applications of vasoprobes throughout the brain. In Aim 2, we will optimize vasoprobes to sense the key neurotransmitters dopamine and glutamate; we will then apply them on a brain-wide scale for molecular-level fMRI in rodent brains. These experiments, in conjunction with outcome of Aim 1, will set the stage for applications of neurotransmitter-sensitive vasoprobes and related sensors in primate brains. Accord- ingly, in Aim 3, we will adapt neurotransmitter-sensitive vasoprobe technology for functional molecular neuroim- aging in marmosets, a tractable primate species with which we have previous experience. Successful completion of validation experiments in marmosets will therefore establish groundbreaking imaging agents suitable for trans- lation to humans, as well as for adaptation to many further neurophysiological targets.

我们建议开发一种以分子精度监测人脑功能的探针技术。 结合磁共振成像（MRI）或其他成像方式，问题将提供 敏感性和解决方案的结合，可以允许对动态性化的前所未有的无创研究 人的ro恋过程。我们的策略是基于一种从根本上新型的化学成像 探针通过故意操纵内源性血流动力学来产生神经成像读数 大脑中的对比 - 依靠传统基础的血氧水平依赖（粗体）效应（粗体） 功能性MRI（fMRI）。这个新的“血管探针”概念提供了三个关键优势：首先，通过提供时间de-- 对稀释分子物种（例如神经递质）的敏感性，这些问题可以实现明确的定义 神经生物学现象将在整个大脑中动态映射，急剧超越现有 非特异性fMRI方法。其次，由于它们影响的内源性对比来源，问题 通过非侵入成像模态完工，可以在各种时空尺度上检测到fMRI， 例如弥漫性光学或超声基方法。第三，通过规避既定光学的局限 磁性和放射性探针设计，血管探针结合了一个接近正电子的敏感性 发射断层扫描（PET）具有MRI的分辨率和多功能性。在这个项目中，我们将基于最新 概念证明与血管探针合作，以建立无创脑室的交付策略并制定 在原发性中起作用的强大神经化学传感器。我们建立的技术将解决多个目标 在基本和应用的神经科学中，我们预计它会产生适合临床的分子问题 在项目期结束之前对人类受试者进行评估。 在AIM 1中，我们将创建可以通过静脉注射和 通过血脑屏障（BBB）的赞助渗透。我们将形成基于血管探针的共轭物 具有“大脑穿梭”抗体的传感器以前已显示可通过接收器进口大脑 - 介导的转胞病。脑渗透探测器的演示将建立临床上可行的路径 整个大脑中的血管探针的轻松，无创应用。在AIM 2中，我们将优化血管探针 感知关键的神经递质多巴胺和谷氨酸；然后，我们将以大脑范围应用它们 啮齿动物大脑中的分子级fMRI。这些实验以及AIM 1的结果结合了 在原发性大脑中应用神经递质敏感的血管探测器和相关传感器的应用。符合- 在AIM 3中，我们将适应神经递质敏感的血管探针技术用于功能分子神经膜 摩尔莫斯群岛（Marmosets）的老化，这是我们以前具有经验的可寓言主要物种。成功完成 因此 向人类以及适应许多进一步的神经生理靶标。