Translational PET imaging evaluation of [18F]Favipiravir by positron emission tomography

ABSTRACT

Objectives: With over 90 million cases reported in the globe, the COVID-19 pandemic caused by SARS-CoV-2 has been a serious public health crisis. Development of novel and specific antiviral drugs against the SARS-CoV-2 has been an urgent demand. One such drug is Favipiravir, initially developed as an antiviral drug against influenza. Now Favipiravir has received approvals for emergency use against SARS-CoV-2 in many countries. A better understanding of Favipiravir’s biodistribution and pharmacokinetics in vivo will facilitate the clinical development of antiviral drugs against the SARS-CoV-2. Herein, we reported the evaluation of [18 F]Favipiravir with PET in cross-species studies to demonstrate the drug’s biodistribu-tion and pharmacokinetics and investigate the potentially increased risk of neurodegenerative diseases and/or neuroinflammation to COVID-19. Methods: The radiosynthesis of [18 F]Favipiravir was via labeling a commercially available precursor, methyl-5-chloroisoxazolo[4,5-b] pyrazine-3-carboxylate with K[18F]F/K222 and K2CO3 in DMSO at 130°C for 10 min, followed by hydrolysis with NaOH (aq.) at 110°C for 15 min.1 The whole body distribution on CD-1 mice was performed at four time points (5, 15, 30, 60 min). PET studies were carried out in CD-1 mice and AD mice (5XFAD) and naïve rhesus monkeys. We also performed the radiometabolite analysis of [18 F]Favipiravir in plasma and brain of CD-1 mice at 30 min post-injection. Results: [18 F]Favipiravir was obtained in 29% isolated radiochemi-cal yield (decay corrected). The radiochemical purity of the tracer was greater than 99%. No sign of radiolysis was observed for [18F] Favipiravir up to 120 min after formulation with 10% EtOH/saline. High radioactivity accumulation was observed in blood, lung, liver, kidney, and bone (around or more than 5% ID/g, injected dose per gram of wet tissue). The radioactivity level reached a plateau in small intestine, kidney and liver at 30,15 and 5 min, respectively, followed by slow washout, indicating that [18F]Favipiravir was possibly eliminated via the hepatobiliary and urinary pathway. For the radio-metabolic analysis of [18F]Favipiravir, average 41% and 89% of the radioactivity was parent fraction in the mice brain and plasma at 30 min post-injection (n=2), respectively. In PET imaging of CD-1 mice, the standard uptake value (SUV) of [18F]Favipiravir in brain reached its max value of 0.5 at 10 min and slowly reduced to 0.4 at 60 min. The results of PET imaging of AD mice with [18 F]Favipiravir were similar with that of CD-1 mice. In PET imaging of Rhesus monkeys, the brain uptake of [18 F]Favipiravir reached the max value of 0.5 SUV at 5 min and subsequently decreased to 50-60% of the maximum at 60 min. Conclusion: The evaluation of [18F]Favipiravir has demonstrated with bio-distribution and PET in mice and NHPs. Further evaluation of pharmacokinetics of [18F]Favipiravir in whole body monkey scans and LPS-induced neuroinflammation models is underway.