Evaluation of [18F]Favipiravir with PET in Naive and transgenic AD mouse models

Introduction: With the spread of the SARS-CoV-2 in the past two years, over 300 million infected cases have been reported and the COVID-19 pandemic has become a serious public health crisis in the world. For treating SARS-CoV-2 infections, specific antiviral drugs have been regarded as a potential treatment. As an antiviral drug against influenza, Favipiravir was considered as an anti-SARS-CoV-2 drug in trials as a potential treatment of COVID-19. And Favipiravir has been approved for emergency use as the treatment of COID-19 in different countries. A better understanding of in vivo biodistribution and pharmacokinetics of Favipiravir should facilitate the development of antiviral drugs against the SARS-CoV-2, particularly for neurodegenerative diseases, including Alzheimer's disease. Herein, we reported the evaluation of [¹⁸F]Favipiravir with PET in naive mice and transgenic AD mouse models to investigate in vivo biodistribution and pharmacokinetics of Favipiravir and the potential comorbid risk of neurodegenerative disease to COVID-19.

Methods: The [¹⁸F]Favipiravir was synthesized via ¹⁸F-fluorination of precursor, methyl-5-chloroisoxazolo[4,5-b] pyrazine-3-carboxylate with K[¹⁸F]F/K222 and K₂CO₃ as the base in DMSO at 130 ^oC for 10 min, followed by hydrolysis with NaOH (0.5 N in water) at 110 ^oC for 15 min.¹ The whole body biodistribution was performed on CD-1 mice at four time points (5, 15, 30, 60 min). Dynamic PET imaging studies were carried out on CD-1 mice and AD mice. The radiometabolite analysis of [¹⁸F]Favipiravir in plasma and brain was performed on CD-1 mice at 30 min post-injection.

Results: [¹⁸F]Favipiravir was synthesized in 29% isolated radiochemical yield (decay corrected) with the radiochemical purity greater than 99%, and no obvious decompositions of [¹⁸F]Favipiravir was observed up to 120 min after formulation with saline (5% EtOH). In biodistribution study, 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 in kidney, liver, and small intestine, reached a plateau at 15,5 and 30 min, respectively, followed by slow washout, indicating that [¹⁸F]Favipiravir was possibly eliminated via the urinary and hepatobiliary pathway. In the radiometabolite analysis of [¹⁸F]Favipiravir, average 41% and 89% of the radioactivity were parent fractions in the CD-1 mice brain and plasma at 30 min post-injection (n = 2), respectively. In dynamic PET imaging studies with 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. In dynamic PET imaging studies with AD mice and WT mice, no significant difference was found in distribution of [¹⁸F]Favipiravir between AD mice and WT mice.

Conclusions: The evaluation of [¹⁸F]Favipiravir has demonstrated with in vivo bio-distribution and PET in CD-1 mice and AD mice. In vivo biodistribution, clearance of [¹⁸F]Favipiravir via kidney, liver, and small intestine indicates its elimination via urinary and hepatobiliary pathway. In dynamic PET imaging studies, no significant difference was found in distribution of [¹⁸F]Favipiravir between AD mice, WT mice and CD-1 mice.

• Download figure
• Open in new tab
• Download powerpoint