Development of 18F PET radiotracers for M2 microglia as diagnostics for multiplesclerosis pathogenesis

开发用于 M2 小胶质细胞的 18F PET 放射性示踪剂作为多发性硬化症发病机制的诊断

• 批准号: 10440539
• 负责人: Paul Anthony Stupple
• 金额: $ 28.82万
• 依托单位: MONASH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440539
• 关键词: ABCG2 gene; Adult; Affect; Affinity; Animal Model; Anti-Inflammatory Agents; Autoradiography; Binding; Binding Sites; Biological Markers; Biological Process; Brain; C57BL/6 Mouse; Caucasians; Cells; Clinical; Clinical Research; Clinical Trials; Cuprizone; Development; Diagnostic; Diagnostic Reagent; Digit structure; Disease; Disease Outcome; Dose; Equipment; Exhibits; FLT3 gene; Failure; Fluorides; Fluorine; Freezing; Future; Genes; Image; Immune; Immunohistochemistry; In Vitro; Inflammatory; Inflammatory Response; Injury; Kinetics; Laboratories; Lead; Lesion; Ligands; Link; MERTK gene; Measures; Mediator of activation protein; Medical Care Costs; Microglia; Modeling; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Nature; Nerve Degeneration; Nervous system structure; Outcome; Pathogenesis; Pathogenicity; Patients; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Positron-Emission Tomography; Predisposition; Property; Proteins; Radioactive; Radiochemistry; Receptor Protein-Tyrosine Kinases; Rodent; Route; Scanning; Signal Transduction; Slice; Solubility; Stratification; Structure; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Tracer; Translational Research; Variant; Work; blood-brain barrier permeabilization; cytokine; design; diagnostic tool; differential expression; disability; economic cost; imaging approach; improved; in vivo; kinase inhibitor; macrophage; mouse model; multiple sclerosis patient; nanomolar; nervous system disorder; next generation; non-invasive imaging; novel; patient stratification; radiochemical; radioligand; radiotracer; repaired; response; response to injury; selective expression; success; tool; treatment response; treatment strategy; uptake; young adult

Project summary Multiple sclerosis (MS) is the most common disabling neurodegenerative condition that affects young adults around the world. Despite enormous efforts for treatment discovery, progressive disability, accompanied by very significant adverse personal, medical and economic costs, remains very common. An important reason that contributes to the unenviable track record of clinical trial failure for progressive MS is our inability to monitor in a precise manner the status of MS at any given time. Although it has been established that the inflammatory cells within the brain, known as microglia, are active in the progressive phase of the disease and most likely dictate outcome, we remain unable to differentiate between MS-mediator and reparative microglia. Therefore, there is a dire need to develop techniques that identify the subsets of microglia in order to stratify patients and offer them adequate treatment. Positron emission tomography (PET) has recently gained huge success as a non-invasive imaging approach to accurately quantify biological processes within the brain. Thus far, PET imaging in MS patients has been restricted to imaging a radioactive molecule, i.e. radioligand, that binds to a protein known as TSPO. However, the recently observed variation of the TSPO gene, with some patients lacking binding of the radioligands, and its inability to distinguish the activity of microglia limits its utility as a clinical and research tool. Building on our previous results showing the selective upregulated expression of a protein by reparative microglia, we will develop radioligands that bind to this protein and can be used for diagnostic purposes via PET. This highly translational research plan will enable clinicians to classify MS in novel ways to guide therapeutic intervention in MS patients in ways not previously possible. The specific aims of this project are to (i) design and synthesize next-generation radioligands with optimized binding and CNS penetration; (ii) generate radioactive versions of leading compounds; (iii) validate the radioligands in MS mouse brain slices and assess them by PET in MS mouse models. Outcome: This work will result in a diagnostic reagent that, using imaging equipment, will help clinicians monitor the status of progressive MS in patients being treated in a manner that has never been possible before and improve the success rates of new MS drugs being tested in clinical trials.

项目概要 多发性硬化症 (MS) 是影响年轻人的最常见的致残性神经退行性疾病 世界各地。尽管为发现治疗方法付出了巨大的努力，但渐进性残疾并伴随着非常严重的症状 严重的个人、医疗和经济损失仍然很常见。一个重要原因是 进展性多发性硬化症的临床试验失败的一个令人羡慕的记录是我们无法监测 精确地了解 MS 在任何给定时间的状态。尽管已经确定炎症细胞 大脑内的小胶质细胞在疾病的进展阶段很活跃，很可能决定 结果，我们仍然无法区分 MS 介导细胞和修复性小胶质细胞。因此，有 迫切需要开发识别小胶质细胞亚群的技术，以便对患者进行分层并为他们提供服务 充分的治疗。 正电子发射断层扫描（PET）作为一种非侵入性成像方法最近取得了巨大成功 准确量化大脑内的生物过程。迄今为止，多发性硬化症患者的 PET 成像已 仅限于对与 TSPO 蛋白质结合的放射性分子（即放射性配体）进行成像。然而， 最近观察到的 TSPO 基因变异，一些患者缺乏放射性配体的结合，以及 它无法区分小胶质细胞的活动限制了其作为临床和研究工具的实用性。建立在我们的 先前的结果显示修复性小胶质细胞选择性上调蛋白质的表达，我们将 开发与该蛋白质结合的放射性配体，并可通过 PET 用于诊断目的。这高度 转化研究计划将使临床医生能够以新颖的方式对多发性硬化症进行分类，以指导治疗干预 以以前不可能的方式治疗多发性硬化症患者。 该项目的具体目标是（i）设计和合成具有优化的下一代放射性配体 结合和中枢神经系统渗透； (ii) 产生先导化合物的放射性版本； (iii) 验证 多发性硬化症小鼠脑切片中的放射性配体，并通过 PET 在多发性硬化症小鼠模型中对其进行评估。 结果：这项工作将产生一种诊断试剂，使用成像设备，将帮助临床医生监测 以以前不可能的方式治疗的患者的进展性多发性硬化症的状态 提高多发性硬化症新药临床试验的成功率。