F-18 labelled PET tracer for imaging macrophage colony stimulating factor 1 receptor (CSF1R) in neuroinflammation

F-18 标记的 PET 示踪剂，用于神经炎症中巨噬细胞集落刺激因子 1 受体 (CSF1R) 的成像

基本信息

批准号：
9912886
负责人：
Andrew G Horti
金额：
$ 61.79万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912886
关键词：
Address Affinity Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease therapy Amyloid beta-Protein Animal Model Animals Astrocytes Automation Autopsy Autoradiography Binding Binding Sites Brain Cells Central Nervous System Diseases Cerebrum Characteristics Chronic Clinical Data Diagnosis Disease Ensure Exhibits Functional disorder Funding Future Generations Genotype Goals HIV Half-Life Health Human Image In Vitro Industry Collaboration Inflammatory Kinetics Label Lead Lipopolysaccharides Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Malignant neoplasm of brain Measurement Measures Mediator of activation protein Medical Metabolic Methods Microglia Modeling Monitor Multiple Sclerosis Mus Neuroglia Neurons Pain Papio Pathogenesis Patients Phenotype Positron-Emission Tomography Procedures Property Proteins Radiation Radioisotopes Radiometry Research Personnel Running Safety Sensitivity and Specificity Specificity Stroke Structure Testing Therapeutic Toxicology Tracer Translations Traumatic Brain Injury Validation Work analog cell type dosimetry drug development human disease human subject imaging agent imaging properties in vivo imaging inflammatory milieu multi-site trial neuroinflammation nonhuman primate outcome forecast pre-clinical preclinical study radiotracer receptor density success targeted imaging targeted treatment uptake

项目摘要

Success has eluded trials that have focused on anti-Aβ therapies for Alzheimer’s disease (AD), necessitating consideration of other clinical targets or multi-target approaches. One such target on which we have been focusing is neuroinflammation, which is increasingly recognized as a key mediator in the pathogenesis of AD. We have used imaging in vivo with positron emission tomography (PET) to assess glial cell activity, which is disrupted in AD, where neuroinflammation, and in particular microglia, are chronically activated to promote a continually pro-inflammatory milieu. Our colleagues have shown that microglia induce astrocytes to an A1 pro-inflammatory phenotype that is toxic to neurons. We have recently discovered the first and only PET imaging agent, [11C]CPPC, that is specific for microglia by engaging the macrophage colony stimulating factor-1 receptor (CSF1R). Post-mortem studies have shown highly increased expression of cerebral CSF1R in patients with AD. Our present goal is to validate a second-generation, more commercially viable CSF1R PET imaging agent, [18F]JHU12809, in a non-human primate model of neuroinflammation and post-mortem human brain (healthy and AD). Ultimately we will use this agent to enable development of drugs that address the neuroinflammatory component of AD. As an initial step toward validation, the proposed imaging project addresses measurement of the availability and distribution of CSF1R within the baboon brain under neuroinflammatory conditions (Aim 1). In a graded approach we will complete pre-clinical studies with [18F]JHU12809 including assessment of radiometabolites and calculation of dosimetry estimates (Aim 2), optimization and automation of the radiosynthesis (Aim 3) and determination of CSF1R density in post-mortem healthy and AD brains (Aim 4). We have obtained independent funding for the toxicology studies also needed for the eIND. Upon completion of this project we will have validated an 18F-labeled radiotracer targeting CSF1R, increasingly recognized as a specific marker of microglia within the brain, ready to be applied to AD and potentially other conditions not heretofore studied directly and non-invasively in human subjects. Notably, [18F]JHU12809, the test article in the proposed studies, is even more specific for CSF1R than our recent lead, [11C]CPPC. The longer physical half-life of [18F]JHU12809 will enable widespread translation and dissemination through academic and industry collaboration.

专注于治疗阿尔茨海默病 (AD) 的抗 Aβ 疗法的试验未能取得成功，因此需要考虑其他临床靶点或多靶点方法，我们一直关注的一个靶点就是神经炎症，它越来越被认为是一个关键。我们使用正电子发射断层扫描 (PET) 进行体内成像来评估神经胶质细胞的活性，该活性在 AD 中受到破坏，其中神经炎症，特别是小胶质细胞，我们的同事已经证明，小胶质细胞会诱导星形胶质细胞产生对神经元有毒的 A1 促炎表型。通过与巨噬细胞集落刺激因子 1 受体 (CSF1R) 结合，对小胶质细胞具有特异性。尸检研究表明，AD 患者脑部 CSF1R 的表达显着增加。商业上可行的 CSF1R PET 显像剂 [18F]JHU12809，用于神经炎症和死后人脑（健康和 AD）的非人类灵长类动物模型，最终我们将使用该试剂来开发解决神经炎症成分的药物。广告。作为验证的第一步，拟议的成像项目致力于测量神经炎症条件下狒狒大脑内 CSF1R 的可用性和分布（目标 1），我们将采用分级方法完成 [18F]JHU12809 的临床前研究，包括评估。放射代谢物的分析和剂量测定估计的计算（目标 2）、放射合成的优化和自动化（目标 3）以及 CSF1R 密度的测定死后健康和 AD 大脑（目标 4）。我们已经获得了 eIND 所需的毒理学研究的独立资金。该项目完成后，我们将验证一种针对 CSF1R 的 18F 标记放射性示踪剂，它越来越被认为是一种特定标记。大脑内的小胶质细胞，准备应用于 AD 和迄今为止尚未在人类受试者中直接和非侵入性研究的潜在其他疾病。值得注意的是，[18F]JHU12809，即测试文章。拟议的研究比我们最近的领先研究 [11C]CPPC 更具体。[18F]JHU12809 的物理半衰期较长，将通过学术和行业合作实现广泛的翻译和传播。