PET Probes for Senescence Detection in Brain

用于大脑衰老检测的 PET 探针

• 批准号: 10709903
• 负责人: Lina Cui
• 金额: $ 20.47万
• 依托单位: SENOTRAC BIOTECHNOLOGY LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709903
• 关键词: Age; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Disease Models; Animal Model; Animals; Astrocytes; Binding; Biological Markers; Brain; Brain Injuries; Cancer Center; Cell Aging; Cell Cycle Arrest; Cells; Chronic; Clinical; Clinical Trials; Detection; Development; Diagnostic Procedure; Diffusion; Disease; Disease Marker; Early Diagnosis; Evaluation; Excision; Florida; Future; Goals; Homeostasis; Human; Image; Image Analysis; In Vitro; Inflammatory; Legal patent; Link; Molecular; Molecular Probes; Molecular Target; Mus; Neuroglia; Penetration; Persons; Pharmacologic Substance; Phase; Population; Positron-Emission Tomography; Proteins; Radiochemistry; Research; Resolution; Screening procedure; Senile Plaques; Series; Signal Transduction; Site; Specificity; Stress; Technology; Time; Toxic effect; Tracer; Translating; Universities; Work; X-Ray Computed Tomography; age group; age related; aged; aging brain; aging population; beta-Galactosidase; beta-galactoside; blood-brain barrier crossing; brain cell; brain tissue; chemical synthesis; clinically relevant; cognitive function; commercialization; design; detection sensitivity; diagnostic tool; disease phenotype; imaging modality; imaging probe; improved; in vivo; mental function; mouse model; non-invasive imaging; noninvasive diagnosis; novel; pressure; public health relevance; rational design; real-time images; risk stratification; senescence; tau Proteins; therapeutic target; tool; uptake; Age; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Disease Models; Animal Model; Animals; Astrocytes; Binding; Biological Markers; Brain; Brain Injuries; Cancer Center; Cell Aging; Cell Cycle Arrest; Cells; Chronic; Clinical; Clinical Trials; Detection; Development; Diagnostic Procedure; Diffusion; Disease; Disease Marker; Early Diagnosis; Evaluation; Excision; Florida; Future; Goals; Homeostasis; Human; Image; Image Analysis; In Vitro; Inflammatory; Legal patent; Link; Molecular; Molecular Probes; Molecular Target; Mus; Neuroglia; Penetration; Persons; Pharmacologic Substance; Phase; Population; Positron-Emission Tomography; Proteins; Radiochemistry; Research; Resolution; Screening procedure; Senile Plaques; Series; Signal Transduction; Site; Specificity; Stress; Technology; Time; Toxic effect; Tracer; Translating; Universities; Work; X-Ray Computed Tomography; age group; age related; aged; aging brain; aging population; beta-Galactosidase; beta-galactoside; blood-brain barrier crossing; brain cell; brain tissue; chemical synthesis; clinically relevant; cognitive function; commercialization; design; detection sensitivity; diagnostic tool; disease phenotype; imaging modality; imaging probe; improved; in vivo; mental function; mouse model; non-invasive imaging; noninvasive diagnosis; novel; pressure; public health relevance; rational design; real-time images; risk stratification; senescence; tau Proteins; therapeutic target; tool; uptake

PROJECT SUMMARY Around 50 million people worldwide are suffering from Alzheimer’s disease (AD) and related dementias, and AD is observed primarily in aged people. Current diagnosis of AD relies primarily on observations of declines in mental and cognitive functions, when irreversible brain damage occurs. Positron emission tomography (PET) tracers for early diagnosis of AD have been developed via assessing Aβ or tau levels, however aggregate-targeting tracers often suffer from high nonspecific binding. Therefore, there is an urgent need for developing novel tools targeting molecular level to improve the specificity of early diagnosis of AD. Cellular senescence has been shown to be a critical contributor disrupting the homeostasis and functions of aging brains. In aged brains, senescent cells accumulate and exert chronic inflammatory pressure on surrounding cells. Higher levels of senescence in different types of brain cells have been observed in mice and human with AD and selective removal of senescent cells reduces Aβ plaque formation in mouse brain and improves cognitive functions. These findings indicate that senescence can potentially serve as an early indicator and therapeutic target for AD. However, tools for real-time in vivo senescence detection are extremely limited. Recently, the Cui group at the University of Florida (UF) has developed a series of activatable molecular probes, enabling the successful real-time imaging of senescence in animal models for the first time. These probes have high detection sensitivity produced by a self-immobilizing moiety installed on the probe so that upon activation, the probe can be covalently linked to surrounding proteins at the site of activation. Based on this strategy, SenoTrac, partnering with UF and Moffitt Cancer Center, aims to develop the first- in-class PET probes for senescence. Briefly, the novel PET probe will consist of a β-galactoside that can be specifically cleaved by senescence-associated β-galactosidase (SA-β-gal), a 18F, and a self-immobilizing moiety that can anchor the probe onto surrounding proteins upon activation. We expect the activatable PET probe to have high brain uptake, minimal diffusion and high signal/background contrast with excellent spatial resolution. We will characterize these probes in vitro (SenoTrac and UF), and we will also evaluate their ability to cross the blood brain barrier in animals (UF). Radiochemistry before PET imaging will be carried at Moffitt. AD mouse model (5xFAD) will be used in the dynamic PET/CT scan to see the levels of senescence in different age groups. Additionally, we will clear senescent cells using senolytics, perform PET imaging of senescence and evaluate AD phenotypes in these mice. Ex vivo analysis of the brain tissues will provide information of other AD and senescence biomarkers (UF). We expect to draw correlation of senescence levels and various AD phenotypes. In Phase 1, we will develop the PET probes for senescence tracking in AD animal models. In Phase 2, we will evaluate the probes in different animal models, and a small-scale human trial. We will navigate the regulatory requirements, and work towards commercialization of these probes.

项目摘要 全球约有5000万人患有阿尔茨海默氏病（AD）和相关痴呆症， 广告主要在老年人中观察到。当前的广告诊断主要依赖于观察 当发生不可逆的脑损伤时，精神和认知功能的下降。正电子发射 通过评估Aβ或TAU水平开发了用于早期诊断AD的层造影仪（PET）示踪剂， 但是，键入的示踪剂通常会受到高非特异性结合的影响。因此，有一个紧急的 需要开发针对分子水平的新型工具以提高AD早期诊断的特异性。 细胞感应已被证明是破坏稳态和功能的关键因素 衰老的大脑。在老化的大脑中，感觉细胞会积累并施加慢性炎症压力 周围的细胞。在小鼠和 与AD的人类和选择性去除感觉细胞可减少小鼠脑中的Aβ斑块形成 提高认知功能。这些发现表明，感应可能有可能用作早期指标 和AD的热目标。但是，实时体内感应检测的工具非常有限。 最近，佛罗里达大学（UF）的CUI小组开发了一系列可激活的分子问题，即 首次实现动物模型中感应的成功实时成像。这些问题有 由安装在探针上的自杀部分产生的高检测灵敏度，使其在激活后， 探针可以共价链接到激活部位的周围蛋白质。 基于这一策略，Senotrac与UF和Moffitt癌症中心合作，旨在发展第一 室内PET探针以进行感应。简而言之，新型的PET探针将由β-半乳糖苷组成，可以是 特别是通过感应相关的β-半乳糖苷酶（SA-β-GAL），A 18F和自动杀伤的特殊裂解 激活后可以将探针锚定在周围蛋白质上的部分。我们期望有可激活的宠物 探针具有高脑吸收，最小扩散和高信号/背景与优秀的空间形成鲜明对比 解决。我们将在体外表征这些问题（Senotrac和UF），我们还将评估它们的能力 跨越动物的血液屏障（UF）。宠物成像之前的放射化学将在莫菲特（Moffitt）进行。 AD小鼠模型（5XFAD）将用于动态PET/CT扫描中，以查看在 不同的年龄组。此外，我们将使用鼻溶剂清除感觉细胞，执行PET成像 这些小鼠的感受和评估AD表型。脑组织的体内分析将提供 其他AD和感应生物标志物（UF）的信息。我们期望吸引感应水平的相关性 和各种AD表型。在第1阶段，我们将发展AD动物的宠物问题以进行感应跟踪 型号。在第2阶段，我们将评估不同动物模型中的问题和小型人类试验。我们 将浏览监管要求，并致力于这些问题的商业化。