PET Probes for Senescence Detection in Brain

项目总结 全球约有5000万人患有阿尔茨海默病(AD)和相关痴呆症， AD主要见于老年人。目前AD的诊断主要依赖于对 当发生不可逆转的脑损伤时，智力和认知功能下降。正电子发射 已经开发了用于AD早期诊断的断层扫描示踪剂，通过评估Aβ或tau水平， 然而，聚集靶向示踪剂往往受到高度非特异性结合的影响。因此，当务之急是 需要开发新的靶向分子水平的工具来提高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。 大脑老化。在老年人的大脑中，衰老的细胞积累并对其施加慢性炎症压力 周围的细胞。在不同类型的脑细胞中观察到更高水平的衰老 患有AD并选择性移除衰老细胞的人减少了小鼠脑内β斑块的形成 改善认知功能。这些发现表明，衰老可以潜在地作为早期指标。 和AD的治疗靶点。然而，用于实时体内衰老检测的工具极其有限。 最近，佛罗里达大学的崔小组开发了一系列可激活的分子探针， 首次实现了对动物模型衰老的成功实时成像。这些探测器有 通过安装在探头上的自固定部分产生高检测灵敏度， 该探针可以在激活部位与周围的蛋白质共价连接。 基于这一战略，SenoTrac与UF和莫菲特癌症中心合作，旨在开发第一个- 针对衰老的同类PET探头。简而言之，这种新型的正电子发射体层析探针将由β-半乳糖苷组成，它可以 被衰老相关的β-半乳糖苷酶(SA-β-GAL)、18F和自我固定的 部分可以在激活时将探针锚定在周围的蛋白质上。我们期待可激活的PET 探头具有高脑摄取率、最小扩散和高信号/背景对比度，空间效果极佳 决议。我们将在体外对这些探针(SenoTrac和UF)进行表征，并评估它们的能力 通过动物的血脑屏障(UF)。PET成像前的放射化学将在莫菲特进行。 AD小鼠模型(5xFAD)将用于动态PET/CT扫描，以了解 不同的年龄段。此外，我们将使用促衰老物质清除衰老细胞，进行PET成像 并评估这些小鼠的AD表型。对脑组织的体外分析将提供 其他AD和衰老生物标志物(UF)的信息。我们希望得出衰老程度之间的关联 和各种AD表型。在第一阶段，我们将开发用于追踪AD动物衰老的PET探针 模特们。在第二阶段，我们将在不同的动物模型中评估这些探针，并进行小规模的人体试验。我们 将满足监管要求，并努力实现这些探测器的商业化。

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.