β-[18F]Fluoro Azomycin Arabinoside (β-[18F]FAZA): Synthesis, Radiofluorination and Preliminary PET Imaging of Murine A431 Tumors

Background: 1-α-D-(5-Deoxy-5-[¹⁸F]fluoroarabinofuranosyl)-2-nitroimidazole([¹⁸F] FAZA) is a PET radiotracer that demonstrates excellent potential in imaging regional hypoxia, and is clinically used in diagnosing a wide range of solid tumors in cancer patients. [¹⁸F]FAZA, however, is radiofluorinated in only moderate recovered radiochemical yield (rRCY, ~12%). It is postulated that the relative stability of the C1' β-anomeric bond at C5' will make 1-β-D-(5-fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole (β-FAZA), the β-conformer of FAZA, an attractive candidate for clinical hypoxia imaging. Objectives: The principle goals were to synthesize β-FAZA and β-Ac2TsAZA, the radiofluorination precursor, to establish the radiofluorination chemistry leading toβ-[¹⁸F]FAZA, and to investigate the biodistribution of β-[¹⁸F]FAZA in an animal tumor-bearing model using PET imaging. Methods: The appropriately-protected furanose sugar was coupled with 2-nitroimidazole to afford 1-β-D-(2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2AZA). Fluorination of β-Ac2AZA with DAST, followed by alkaline hydrolysis, afforded β-FAZA (21%). The radiolabeling synthon, 1-β-D-(5-O-toluenesulfonyl-2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2TsAZA), on radiofluorination using the ¹⁸F/K222 complex under various reaction conditions, followed by base-catalyzed deacetylation, afforded β-[¹⁸F]FAZA. β-[¹⁸F]FAZA was radiochemically stable for at least 8 h when stored in aqueous ethanol (8%) at 22 °C. A preliminary PET imaging-based biodistribution study of β-[¹⁸F]FAZA was performed in A431 tumor-bearing nude mice. Results: β-FAZA and β-Ac2TsAZA were synthesized in satisfactory yield. Radiochemistry of [¹⁸F]FAZA was established. PET images showed strong uptake in hypoxic regions of the tumor. Conclusion:The synthesis of β-FAZA and β-[18F]FAZA are reported. Radiofluorination of β-Ac2TsAZA and the deprotection of β-Ac2[18F]FAZA were facile, but led to a more complex mixture of radiofluorinated by-products than observed with the corresponding precursor of β-[18F]FAZA. PET images were indicative of hypoxia-selective accumulation of β-[18F]FAZA in tumor.>