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Synthesis of [18F]Favipiravir and Biodistribution in C3H/HeN Mice as Assessed by Positron Emission Tomography.

ABSTRACT: Favipiravir (T705; 6-fluoro-3-hydroxypyrazine-2-carboxamide) is a pyrazine analog that has demonstrated potent antiviral activity against a broad spectrum of viruses in multiple in vivo disease models. To better understand the compounds anti-viral activity, assessment of the drug's biodistribution and kinetics in vivo may lend insight into how best to evaluate the compound efficacy preclinically and to contribute to the design of clinical studies to take into account the compound's pharmacokinetic distribution and kinetics. In the current study, a method for synthesis of [18F]favipiravir was developed and the biodistribution in mice naïve to and pre-dosed with favipiravir was assessed by PET and gamma counting of tissue samples. Fluorine-18 labeling of favipiravir was achieved in a one-pot, two-step synthesis using a commercially available precursor, methyl-5-chloroisoxazolo[4,5-b]pyrazine-3-carboxylate, with an overall radiochemical yield of 15-24%, a molar activity of 37-74 GBq/µmol in a 70?minute synthesis time. [18F]favipiravir tissue uptake and distribution was similar in naïve and pre-dosed mice; however, in the pre-dosed animals plasma clearance was more rapid and tissue clearance appeared to be prolonged. In conclusion, application of PET to the evaluation of favipiravir has demonstrated the importance of dosing regimen on the distribution and tissue uptake and clearance of the molecule. Favipiravir is cleared through the kidney as previously reported but the liver and intestinal excretion may also play an important role in compound elimination. Measurement of the tissue uptake of favipiravir as determined by PET may be a more important indicator of a compound's potential efficacy than purely monitoring plasma parameters such as viremia and drug levels.

SUBMITTER: Bocan TM

PROVIDER: S-EPMC6370782 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

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Synthesis of [18F]Favipiravir and Biodistribution in C3H/HeN Mice as Assessed by Positron Emission Tomography.

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