MAGL PET tracer-guided prognosis and neuroprotective therapy for Alzheimer's disease

MAGL PET 示踪剂引导阿尔茨海默病的预后和神经保护治疗

• 批准号: 10169589
• 负责人: Steven H Liang
• 金额: $ 16.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10169589
• 关键词: 2019-nCoV; AD transgenic mice; Address; Affect; Aftercare; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapy; Antiviral Agents; Antiviral Therapy; Back; Biodistribution; Biological Markers; Blood - brain barrier anatomy; Brain; COVID-19; Catalytic Domain; Cessation of life; Chemicals; China; Chloroquine; Clinical; Clinical Treatment; Clinical Trials; Country; DNA-Directed RNA Polymerase; Disease; Disease Outbreaks; Dose; Drug Kinetics; Drug Monitoring; Ebola; Emergency Situation; Evaluation; Functional disorder; Goals; Imaging Device; Immune; Immunohistochemistry; In Vitro; Infection; Inflammation; Influenza A virus; Italy; Japan; Label; Lung; Massachusetts; Mediating; Metabolism; Monitor; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroimmune system; Organ; Oseltamivir; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Placebos; Plasma; Pneumonia; Positron-Emission Tomography; Precision therapeutics; Pyrazinamide; RNA Viruses; RNA-Directed RNA Polymerase; Radioactive; Radiolabeled; Reporting; Resistance; Risk; Safety; Symptoms; Testing; Therapeutic; Time; Tracer; Transgenic Mice; Vaccines; Variant; Virus; Work; base; behavior test; clinical development; clinical investigation; comorbidity; design; dosage; experimental study; human coronavirus; imaging biomarker; improved; in vivo; interest; kinetic model; mouse model; neuroinflammation; non-invasive imaging; novel; outcome forecast; pharmacodynamic biomarker; pilot trial; pre-clinical research; radiotracer; remdesivir; transgenic model of alzheimer disease; treatment planning; tripolyphosphate; uptake

Project Summary: The 2019 novel coronavirus (SARS-CoV-2; COVID-19) has spread rapidly in the global level since its recent identification in patients with severe pneumonia. To date, there is no approved therapy/vaccine to treat human coronaviruses. For instance, there is tentative evidence of Remdesivir for alleviating COVID-19 symptom as authorized for emergency use by the FDA, which is still being tested in advanced clinical trials worldwide. Favipiravir is an anti-viral drug developed by Toyama Chemical of Japan. It is a pyrazinecarboxamide derivative that has been reported to show activities against RNA viruses in vivo and in vitro. Favipiravir is phosphoribosylated to favipiravir-ribofuranosyl-5′-triphosphate, which then recognized as a substrate by RNA-dependent RNA polymerase (RdRp) and inhibits the RNA polymerase activity. Favipiravir is active against influenza A/B/C, including oseltamivir- resistant variants. Some preclinical research has indicated that Favipiravir may have efficacy against Ebola. In February 2020, Favipiravir was being studied in China for COVID-19 treatment. The results showed that patients who had tested positive for COVID-19 and given the drug got a negative virus test back four days after treatment. Lung conditions improved in about 91% of patients taking Favipiravir. In March 2020, a pilot trial suggested that Favipiravir was effective in treating COVID-19 and further clinical trials are underway in Japan (Phase III), Italy (Phase III) and the U.S. (Massachusetts, Phase I). Although Remdesivir and Favipiravir both target RdRp, it is worth mentioning that, compared to Remdesivir, Favipiravir is a fluorinated anti-viral drug, which represents a unique opportunity for studying dosing and target engagement in vivo using its 18F-isotopologue by positron emission tomography (PET). Although preliminary positive outcome has been made in COVID-19 patients with Favipiravir treatment, given that the study was only able to monitor drug changes in plasma levels following treatment, we hypothesize that anti-viral therapy using non-invasive imaging tools could provide the direct and real-time correlation between drug treatment and disease stages via whole body distribution and target occupancy of Favipiravir in organs of interest, such as the brain. PET can provide such information via targeted radioactive molecules (radiotracers; in this work, the tracer is [18F]Favipiravir), which will be highly advantageous in monitoring [18F]Favipiravir exposure in the central nervous system under neurodegenerative conditions comorbid with blood-brain barrier dysfunction/neuroinflammation. Neurodegenerative diseases, including Alzheimer’s disease, are known to disrupt brain integrity and function, thus leading to an increase risk of COVID-19 infection, neuroinflammation and immune compromise, as well as safety concerns for dose selection for anti-viral therapy. In this work, we hypothesize that [18F]Favipiravir can be re-purposed as invaluable pharmacokinetic and/or pharmacodynamic imaging markers for clinical development of anti-viral therapeutics by enabling target occupancy studies in highly-vulnerable brain affected by COVID-19. Such critical information would substantially and rapidly improve our design of anti-viral treatment plans, particularly for treating potential SARS-CoV-2 reservoirs in the CNS.

项目概述：2019年新型冠状病毒(SARS-CoV-2；新冠肺炎)自2019年以来在全球层面迅速传播 它最近在重症肺炎患者中被发现。到目前为止，还没有得到批准的治疗方法/疫苗。 人类冠状病毒。例如，有初步证据表明，雷米西韦可缓解新冠肺炎症状，如 FDA授权紧急使用，目前仍在全球范围内进行高级临床试验。 法维拉韦是日本富山化学公司开发的一种抗病毒药物。它是一种吡嗪甲酰胺的衍生物 据报道，它在体内和体外都显示出抗RNA病毒的活性。法维拉韦的磷酸核糖基化产物 法韦拉韦-呋喃核糖-5‘-三磷酸，然后被依赖于RNA的RNA聚合酶识别为底物 (RdRp)，并抑制RNA聚合酶活性。法维拉韦对甲型/乙型/丙型流感有效，包括奥司他韦。 抗药性变异体。一些临床前研究表明，法比拉韦可能对埃博拉病毒有疗效。在……里面 2020年2月，法维拉韦在中国接受新冠肺炎治疗研究。结果显示，那些 新冠肺炎检测呈阳性，鉴于药物在治疗四天后病毒检测呈阴性。肺 在服用法比拉韦的患者中，大约91%的患者病情有所改善。2020年3月，一项试点试验建议法比拉韦 对治疗新冠肺炎有效，进一步的临床试验正在日本(第三阶段)、意大利(第三阶段)和 美国(马萨诸塞州，第一阶段)。虽然Remdesivir和Favipiravir都针对RdRp，但值得一提的是， 与Remsivir相比，Favipiravir是一种氟化抗病毒药物，这是一个独特的研究机会 通过正电子发射断层扫描(PET)，使用其18F-同位素在体内的剂量和靶向结合。 尽管接受法比拉韦治疗的新冠肺炎患者已取得初步阳性结果，但鉴于 这项研究只能监测治疗后血浆药物水平的变化，我们假设抗病毒 使用非侵入性成像工具的治疗可以提供药物治疗之间的直接和实时关联 和疾病阶段，通过全身分布和目标占有率的法比拉韦在感兴趣的器官，如 大脑。PET可以通过靶向放射性分子(放射性示踪剂；在本工作中，示踪剂是 [18F]Favipiravir)，这将非常有利于监测[18F]Favipiravir在中枢神经系统的暴露 神经变性条件下的系统与血脑屏障功能障碍/神经炎症并存。 众所周知，包括阿尔茨海默氏症在内的神经退行性疾病会破坏大脑的完整性和功能，因此 导致新冠肺炎感染、神经炎症和免疫妥协的风险增加，以及安全 对抗病毒治疗剂量选择的关注。在这项工作中，我们假设[18F]Favipiravir可以被重新使用 作为临床开发抗病毒药物的宝贵药代动力学和/或药效学成像标志物 通过在受新冠肺炎影响的高度脆弱的大脑中进行目标占用研究，治疗。如此挑剔 信息将大大和迅速地改进我们的抗病毒治疗计划的设计，特别是治疗 CNS地区潜在的SARS-CoV-2宿主。