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

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.

项目概要 全球约有 5000 万人患有阿尔茨海默病 (AD) 和相关痴呆症， AD 主要发生在老年人中。目前 AD 的诊断主要依赖于观察 当发生不可逆转的脑损伤时，精神和认知功能会下降。正电子发射 通过评估 Aβ 或 tau 水平，开发出了用于早期诊断 AD 的断层扫描 (PET) 示踪剂， 然而，聚集体靶向示踪剂经常遭受高非特异性结合的困扰。因此，当务之急是 需要开发针对分子水平的新工具来提高 AD 早期诊断的特异性。 细胞衰老已被证明是破坏体内平衡​​和功能的关键因素 老化的大脑。在衰老的大脑中，衰老细胞积聚并对大脑施加慢性炎症压力 周围的细胞。在小鼠和小鼠中观察到不同类型脑细胞的衰老程度较高 患有 AD 的人类和选择性去除衰老细胞可减少小鼠大脑中 Aβ 斑块的形成 改善认知功能。这些发现表明衰老有可能作为早期指标 AD 的治疗靶点。然而，实时体内衰老检测的工具极其有限。 最近，佛罗里达大学（UF）的Cui团队开发了一系列可激活的分子探针， 首次在动物模型中成功实现衰老的实时成像。这些探头有 安装在探针上的自固定部分产生高检测灵敏度，因此在激活后， 探针可以在激活位点与周围蛋白质共价连接。 基于这一战略，SenoTrac 与佛罗里达大学和莫菲特癌症中心合作，旨在开发第一个- 用于衰老的一流 PET 探针。简而言之，新型 PET 探针将由 β-半乳糖苷组成，可 被衰老相关的 β-半乳糖苷酶 (SA-β-gal)、18F 和自固定酶特异性裂解 激活后可以将探针锚定到周围蛋白质上的部分。我们期待可激活的 PET 探针具有高脑摄取、最小扩散和高信号/背景对比度以及出色的空间 解决。我们将在体外表征这些探针（SenoTrac 和 UF），并且我们还将评估它们的能力 穿过动物血脑屏障（UF）。 PET 成像前的放射化学检查将在莫菲特进行。 AD 小鼠模型 (5xFAD) 将用于动态 PET/CT 扫描，以观察小鼠的衰老水平 不同年龄段。此外，我们将使用 senolytics 清除衰老细胞，进行 PET 成像 衰老并评估这些小鼠的 AD 表型。脑组织的离体分析将提供 其他 AD 和衰老生物标志物 (UF) 的信息。我们期望得出衰老水平的相关性 以及各种 AD 表型。在第一阶段，我们将开发用于 AD 动物衰老追踪的 PET 探针 模型。在第二阶段，我们将在不同的动物模型和小规模人体试验中评估探针。我们 将满足监管要求，并致力于这些探针的商业化。

项目成果

Novel PET Imaging Probe for Quantitative Detection of Senescence In Vivo.

• DOI: 10.1021/acs.jmedchem.4c00179
• 发表时间: 2024-03
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Xin Xiang;Chuning Dong;Lianbo Zhou;Jun Liu;Zachary M. Rabinowitz;Yuzhao Zhang;Honghui Guo;Feng He;Xingdou Chen;Yunhua Wang;Lina Cui;Xiaowei Ma