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.

我们建议开发一种探针技术，以分子精度监测人脑功能； 与磁共振成像（MRI）或其他成像方式相结合，探头将提供 灵敏度和分辨率的结合可以实现前所未有的动态神经元非侵入性研究 我们的策略基于一种全新类型的化学成像。 旨在通过有目的地操纵内源性血流动力学来产生神经影像读数的探针 大脑中的对比——重新利用传统基础上的血氧水平依赖（BOLD）效应 这种新的“血管探针”概念具有三个关键优势：首先，通过提供时间延迟。 由于对神经递质等稀释分子种类具有悬而未决的敏感性，探针可以实现明确的 神经生物学现象将在整个大脑中动态映射，大大超越现有的 其次，由于它们影响探针的内源性对比源。 可以通过与功能磁共振成像互补的非侵入性成像方式在各种时空尺度上进行检测， 例如基于漫射光学或超声的方法。第三，通过规避现有光学的局限性， 磁性和放射性探头设计，血管探头巧妙地结合了接近正电子的灵敏度 具有 MRI 分辨率和多功能性的发射断层扫描 (PET) 在这个项目中，我们将在最近的基础上进行发展。 与血管探针进行概念验证，建立无创全脑递送策略并开发 我们建立的技术将实现多个目标。 在基础和应用神经科学领域，我们期望它能产生适合临床的分子探针 项目期结束时对人类受试者进行评估。 在目标 1 中，我们将创建血管探针变体，可以通过静脉注射和 自发渗透通过血脑屏障（BBB） 我们将形成基于血管探针的缀合物。 带有“脑穿梭”抗体的传感器先前已被证明可以通过受体输入大脑 介导的转胞吞作用的示范将建立一个临床上可行的途径。 在目标 2 中，我们将优化血管探针以在整个大脑中轻松、无创地应用。 感知关键的神经递质多巴胺和谷氨酸；然后我们将在全脑范围内应用它们 这些实验与目标 1 的结果相结合，将确定啮齿动物大脑中的分子水平功能磁共振成像。 神经递质敏感血管探针和相关传感器在灵长类动物大脑中的应用阶段。 重要的是，在目标 3 中，我们将采用神经递质敏感血管探针技术来实现功能性分子神经成像 狨猴是一种易于驯服的灵长类动物，我们之前已经成功完成了这一过程。 因此，在狨猴身上进行的验证实验将建立适合反式成像的突破性成像剂。 与人类的关系，以及适应许多进一步的神经生理学目标。