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

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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.