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PET Probes for Senescence Detection in Brain

用于大脑衰老检测的 PET 探针

基本信息

批准号：
10603859
负责人：
Lina Cui
金额：
$ 29.33万
依托单位：
SENOTRAC BIOTECHNOLOGY LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10603859
关键词：
Age Aging Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Animal Disease Models Animal Model Animals Astrocytes Binding Biological Markers Blood - brain barrier anatomy Brain Brain Injuries Cancer Center Cell Aging Cell Cycle Arrest Cells Chemicals Chronic Clinical Clinical Research Clinical Trials Detection Development Diagnostic Procedure Diffuse Diffusion Disease Disease Marker Early Diagnosis Evaluation Excision Florida Future Galactosides Goals Homeostasis Human Image Image Analysis Immobilization In Vitro Inflammatory Legal patent Link Molecular Molecular Probes Molecular Target Mus Neuroglia Penetration Persons Pharmacologic Substance Phase Population Positron-Emission Tomography Proteins Radiochemistry 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 base beta-Galactosidase brain cell brain tissue 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

项目摘要

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.

项目总结