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; 结合磁共振成像（MRI）或其他成像方式，探头将提供 灵敏度和分辨率的结合，可以允许前所未有的动态神经元的非侵入性研究， 人类的生理过程。我们的战略是基于一种全新的化学成像技术 设计用于通过有目的地操纵内源性血流动力学产生神经成像读数的探头 对比脑再利用的血氧水平依赖（BOLD）效应， 功能性磁共振成像（fMRI）。这种新的“血管探针”概念提供了三个关键优点：首先，通过提供时间-时间 对于稀释的分子种类如神经递质的悬垂敏感性，探针可以使明确的 神经生物学现象在整个大脑中动态映射，大大超过现有的 非特异性fMRI方法。第二，由于它们影响的内源性对比源， 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检测， 例如漫射光学或基于超声方法。第三，通过规避现有的光学， 磁和放射性探针设计，血管探针联合收割机结合了接近正电子探针的灵敏度 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，我们将建立在我们最近的 使用血管探针进行概念验证，以建立无创性全脑递送策略，并开发 在灵长类动物中起作用的强大的神经化学传感器。我们建立的技术将解决多个目标 在基础和应用神经科学中，我们希望它能产生适用于临床的分子探针， 在项目期结束前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，可以通过静脉注射输送到大脑， 通过血脑屏障（BBB）的自发渗透。我们将形成基于血管探针的 具有“脑穿梭”抗体的传感器，先前已显示能够通过受体- 介导的转胞吞作用。脑渗透性血管探针的证明将为临床建立一条可行的途径， 血管探针在整个大脑中的简便、非侵入性应用。在目标2中，我们将优化血管探头， 感觉到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， 分子水平的功能磁共振成像。这些实验，结合目标1的结果，将确定 神经递质敏感的血管探针和相关传感器在灵长类动物大脑中的应用阶段。雅阁- 因此，在目标3中，我们将采用神经递质敏感的血管探针技术用于功能性分子神经抑制， 我们以前有过这种经验的灵长类动物--绒猴。成功完成 因此，在绒猴中进行的验证实验将建立适用于反式- 对人类的作用，以及对许多其他神经生理学靶点的适应。