Synthesis, transportability and hypoxiaselective binding of 1-beta-D-(5-Deoxy-5-fluororibofuranosyl)-2-nitroimidazole (beta-5-FAZR), a configurational isomer of the clinical hypoxia marker, FAZA.

Purpose: Cellular uptake of most azomycin- based radiosensitizers depends on perfusion and diffusion, rather than on active transport. In medical imaging using radioisotopically- labeled azomycin nucleosides, image contrast depends on rapid diffusion from normoxic tissues and rapid renal clearance from the central compartment. [ F-18] FAZA [ 1- alpha- D-( 5- deoxy5-[ F-18] fluoroarabinofuranosyl)- 2- nitroimidazole], an azomycin nucleoside currently under clinical evaluation as a marker of tissue hypoxia in medical centers world- wide, provides high contrast but its uptake is diffusion dependent and therefore low. 1-beta- D-( 5- Fluoro- 5- deoxyribofuranosyl)- 2- nitroimidazole 6 ( beta- 5- FAZR), a beta- ribose analog of FAZA, has now been developed to exploit transport across cell membranes to improve absolute uptake in hypoxic regions and high contrast. Methods: beta-5- FAZR was synthesized by classical sugar- base coupling followed by regioselective fluorination. In vitro radiosensitization of hypoxic and normoxic cells to Co-60 x- rays was determined relative to known radiosensitizers. The relative abilities of the human equilibrative nucleoside transporters ( hENT1 & hENT2) and the human concentrative nucleoside transporters, hCNT1, hCNT2 and hCNT3, to bind the radiosensitizers were determined by quantifying their inhibition of [ H-3] uridine transport by recombinant transporters produced in yeast. Results: beta- 5- FAZR was synthesized in 44 percent yield. beta- 5- FAZR had moderate radiosensitization effect on human HCT116/ 100 colorectal carcinoma ( OER 1.8). beta- 5-FAZR was a weak inhibitor of uridine transport relative to non- fluorinated 1- beta- D-( ribofuranosyl)- 2-nitroimidazole ( beta- AZR). Conclusion: Facile synthesis of beta- 5- FAZR was achieved and its activity as a radiosensitizer was confirmed. Substitution of C'- 5 hydroxyl by fluorine in the ribose moiety greatly reduced interaction with hENT1/ 2 and hCNT1/ 2 and moderately reduced interaction with hCNT3 relative to thymidine and beta- AZR.