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

• 批准号: 10390394
• 负责人: Andrew G Horti
• 金额: $ 59.67万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390394
• 关键词: Address; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' 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; Disease associated microglia; 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; Prognosis; Property; Proteins; Radiation; Radioisotopes; Radiometry; Research Personnel; Running; Safety; Sensitivity and Specificity; Specificity; Stroke; 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; pre-clinical; preclinical study; radiotracer; receptor density; success; targeted imaging; targeted treatment; uptake

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.

成功已经避开了专注于阿尔茨海默病（AD）抗A β疗法的试验，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这样的靶点是神经炎症，其越来越被认为是AD发病机制中的关键介质。我们已经使用了体内成像与正电子发射断层扫描（PET），以评估神经胶质细胞的活性，这是破坏AD，其中神经炎症，特别是小胶质细胞，被长期激活，以促进持续的促炎环境。我们的同事已经表明，小胶质细胞诱导星形胶质细胞的A1促炎表型，这是有毒的神经元。我们最近发现了第一个也是唯一的PET成像剂，[11 C]CPPC，它通过与巨噬细胞集落刺激因子-1受体（CSF 1 R）结合而对小胶质细胞具有特异性。尸检研究表明，AD患者的脑CSF 1 R表达高度增加。我们目前的目标是在神经炎症和死后人脑（健康和AD）的非人灵长类动物模型中验证第二代更具商业可行性的CSF 1 R PET显像剂[18 F] JHU 12809。最终，我们将使用这种药物来开发解决AD神经炎症成分的药物。 作为验证的第一步，拟议的成像项目解决了在神经炎症条件下测量狒狒大脑中CSF 1 R的可用性和分布（目标1）。在分级方法中，我们将完成[18 F] JHU 12809的临床前研究，包括放射代谢评估和剂量估计计算（目标2），放射合成的优化和自动化（目标3）以及死后健康和AD大脑中CSF 1 R密度的测定（目标4）。我们已经获得了eIND所需的毒理学研究的独立资金。在完成该项目后，我们将验证一种靶向CSF 1 R的18F标记放射性示踪剂，该示踪剂越来越被认为是大脑内小胶质细胞的特异性标记物，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其他潜在疾病。值得注意的是，[18 F] JHU 12809（拟定研究中的供试品）对CSF 1 R的特异性甚至高于我们最近的先导药物[11 C]CPPC。[18F] JHU 12809较长的物理半衰期将使其能够通过学术和行业合作进行广泛的翻译和传播。