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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要多发性硬化症（MS）是影响年轻人的最常见的残疾神经退行性疾病世界各地。尽管为治疗发现，进行性残疾付出了巨大努力，但巨大的不利个人，医疗和经济成本仍然非常普遍。一个重要的原因为进行性MS的临床试验失败的可爱记录做出贡献是我们无法监视精确方式在任何给定时间的MS状态。尽管已经确定炎症细胞在大脑中，称为小胶质细胞，在疾病的进行性阶段活跃，很可能决定结果，我们仍然无法区分MS-介导者和修复小胶质细胞。因此，有迫切需要开发识别小胶质细胞亚集的技术，以对患者进行分层足够的治疗。正电子发射断层扫描（PET）最近作为一种非侵入成像方法获得了巨大的成功准确量化大脑内的生物过程。到目前为止，MS患者的PET成像已经仅限于成像放射性分子，即放射性分子，该分子与称为TSPO的蛋白质结合。然而，最近观察到的TSPO基因的变化，一些患者缺乏放射性配体的结合，并且它无法区分小胶质细胞的活性限制了其作为临床和研究工具的效用。建立在我们的基础上先前的结果表明选择性上调蛋白质通过修复性小胶质细胞表达，我们将开发与该蛋白质结合的放射性物体，可通过PET用于诊断目的。这很高翻译研究计划将使临床医生能够通过新颖的方式对MS进行分类，以指导治疗干预 MS患者以前无法做到。该项目的具体目的是（i）设计和合成具有优化的下一代放射线结合和中枢神经系统穿透；（ii）生成主要化合物的放射性版本；（iii）验证 MS小鼠脑切片中的放射性聚物，并通过PET在MS小鼠模型中对其进行评估。结果：这项工作将导致诊断试剂，该试剂使用成像设备将帮助临床医生监视在以前从未有可能接受治疗的患者中进行性MS的状态，并且提高在临床试验中测试的新MS药物的成功率。