title: β -[18F]Fluoro Azomycin Arabinoside (β -[18F]FAZA): Synthesis, Radiofluorination and Preliminary PET Imaging of Murine A431 Tumors.
abstract: 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.
  
  
  OBJECTIVE
  The principle goals were to synthesize β-FAZA and β-Ac2TsAZA, the radiofluorination precursor, to establish the radiofluorination chemistry leading to β-[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.
  
  
  CONCLUSIONS
  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 α-[18F]FAZA. PET images were indicative of hypoxia-selective accumulation of β-[18F]FAZA in tumor.
authors.affiliation: Department of Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2. Canada.
authors.forename: Piyush
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Peter McCallum Cancer Institute, Melbourne. Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Roselt
authors.affiliation: Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen. Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Reischl
authors.affiliation: Peter McCallum Cancer Institute, Melbourne. Australia.
authors.forename: Carlene
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: Research Institute for Nuclear Medicine, Tehran University of Medical Sciences, Tehran 14114. Iran.
authors.forename: Davood
authors.initials: D
authors.lastname: Beiki
authors.affiliation: Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen. Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Ehrlichmann
authors.affiliation: Peter McCallum Cancer Institute, Melbourne. Australia.
authors.forename: David
authors.initials: D
authors.lastname: Binns
authors.affiliation: Naimi, Ebrahim Pharmacy Ltd., 9452 118 Ave NW, Edmonton, Alberta. Canada.
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Naimi
authors.affiliation: Department of Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2. Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yang
authors.affiliation: Peter McCallum Cancer Institute, Melbourne. Australia.
authors.forename: Rodney
authors.initials: R
authors.lastname: Hicks
authors.affiliation: Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen. Germany.
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Machulla
authors.affiliation: Department of Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2. Canada.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Wiebe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005462:Fluorine Radioisotopes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging*; D009593:Nitroimidazoles / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry*; D014018:Tissue Distribution; D000072258:Tumor Hypoxia
chemical_list: D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; C498052:fluoroazomycin arabinoside; C006667:azomycin
keywords: FAZA; Hypoxia; PET imaging; [18F]FAZA ; β-FAZA; β-[18F]FAZA