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.

成功的试验旨在研究阿尔茨海默氏病（AD）的抗Aβ疗法，需要考虑其他临床靶标或多目标方法。我们一直在关注的一个目标是神经炎症，越来越多地被认为是AD发病机理中的关键介体。我们已经使用正电子发射断层扫描（PET）的体内成像来评估神经胶质细胞活性，该活性在AD中被破坏，在该AD中，神经炎症，尤其是小胶质细胞被长期激活以促进持续的促炎环境。我们的同事表明，小胶质细胞会诱导星形胶质细胞对神经元有毒的A1促炎表型。我们最近发现了第一种也是唯一的宠物成像剂[11C] CPPC，它通过与巨噬细胞刺激因子1受体（CSF1R）参与而针对小胶质细胞。验尸研究表明，AD患者的脑CSF1R表达高度增加。我们目前的目标是在非人类的神经炎症和人类大脑后的非人类私人模型中验证第二代，更商业上可行的CSF1R宠物成像剂[18F] JHU12809（健康和AD）。最终，我们将使用该药物来开发针对AD神经炎症成分的药物。作为验证的第一步，在神经炎症条件下，提出的成像项目地址测量了CSF1R在狒狒大脑内的可用性和分布的测量（AIM 1）。在分级方法中，我们将使用[18F] JHU12809完成临床前研究，包括评估放射性代谢物以及剂量测定估计值（AIM 2），放射性合成（AIM 3）的优化和自动化（AIM 3）和确定CSF1R的确定CSF1R在健康后健康和AD大脑中的CSF1R密度（AIM 4）。我们已经为毒理学研究获得了独立的资金。该项目完成后，我们将验证针对CSF1R的18F标记的放射性示踪剂，越来越多地被认为是大脑内的小胶质细胞的特定标志物，可以在人类受试者中直接和非侵入性地应用于AD和可能直接和非侵入性的其他条件。值得注意的是，拟议的研究中的测试文章[18F] JHU12809比我们最近的铅[11C] CPPC更具体。 [18F] JHU12809的物理半衰期更长，将通过学术和行业合作来实现宽度的翻译和传播。