title: Synthesis and hypoxia selective radiosensitization potential of beta-2-FAZA and beta-3-FAZL: fluorinated azomycin beta-nucleosides.
abstract: (18)F-Labelled fluoroazomycin arabinoside ([(18)F]FAZA) is a 2-nitroimidazole (azomycin) based PET tracer used extensively in cancer clinics to diagnose tumour hypoxia. The hypoxia-specific uptake and rapid blood clearance kinetics of FAZA contribute to good tumor-to-background ratios (T/B ratios) and high image contrast. However, FAZA, an alpha-configuration nucleoside, is not transported by cellular nucleoside transporters. It enters cells only via diffusion, therefore not achieving the high uptake and T/B ratios characteristic of actively transported radiopharmaceuticals. The present work describes the synthesis, physicochemical properties and preliminary assessment of the radiosensitization properties of two novel azomycin nucleosides, 1-beta-D-(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole (beta-2-FAZA) and 1-beta-D-(3-deoxy-3-fluorolyxofuranosyl)-2-nitroimidazole (beta-3-FAZL) (fluorination yields 60% and 55%, respectively). The tosylated precursors required to synthesize the corresponding F-18 labeled radiopharmaceuticals are also reported. The partition coefficients (P) for beta-2-FAZA (1.0) and beta-3-FAZL (0.95) were marginally lower than reported for FAZA (1.1). The radiosensitization properties of both these compounds are similar to that of FAZA, with sensitizer enhancement ratios (SER) of approximately 1.8 for HCT-116 cells.
authors.affiliation: Department of Oncology, Edmonton PET Centre, Cross Cancer Institute, 11560 University Ave., Edmonton, Canada T6G1Z2. piyushku@cancerboard.ab.ca
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.forename: S
authors.initials: S
authors.lastname: Emami
authors.forename: Z
authors.initials: Z
authors.lastname: Kresolek
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: A J B
authors.initials: AJ
authors.lastname: McEwan
authors.forename: L I
authors.initials: LI
authors.lastname: Wiebe
mesh_terms: D005462:Fluorine Radioisotopes / Q000737:chemistry; D045325:HCT116 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles; D009705:Nucleosides; D011838:Radiation-Sensitizing Agents; C498052:fluoroazomycin arabinoside; C006667:azomycin