[18F]Fluoro-azomycin-2′-deoxy-β-D-ribofuranoside - A new imaging agent for tumor hypoxia in comparison with [18F]FAZA

Introduction: Radiolabeled 2-nitroimidazoles (azomycins) are a prominent class of biomarkers for PET imaging of hypoxia. [F-18]Fluoro-azomycin-alpha-arabinoside ([F-18]FAZA) - already in clinical use - may be seen as alpha-configuration nucleoside, but enters cells only via diffusion and is not transported by cellular nucleoside transporters. To enhance image contrast in comparison to [F-18]FAZA our objective was to F-18-radiolabel an azomycin-2'-deoxyriboside with beta-configuration ([F-18]FAZDR, [F-18]-beta-8) to mimic nucleosides more closely and comparatively evaluate it versus [F-18]FAZA. Methods: Precursor and cold standards for [F-18]FAZDR were synthesized from methyl 2-deoxy-D-ribofuranosides alpha- and beta-1 in 6 steps yielding precursors alpha- and beta-5. beta-5 was radiolabeled in a GE TRACERIab FXF-N synthesizer in DMSO and deprotected with NH4OH to give [18F]FAZDR ([F-18]-beta-8). [F-18]FAZA or [F-18]FAZDR was injected in BALB/c mice bearing CT26 colon carcinoma xenografts, PET scans (10 min) were performed after 1, 2 and 3 h post injection (p.i.). On a subset of mice injected with [F-18]FAZDR, we analyzed biodistribution. Results: [F-18]FAZDR was obtained in non-corrected yields of 10.9 +/- 2.4% (9.1 +/- 2.2 GBq, n = 4) 60 min EOB, with radiochemical purity >98% and specific activity >50 GBq/prnol. Small animal PET imaging showed a decrease in uptake over time for both [F-18]FAZDR (1 h p.i.: 0.56 +/- 022% ID/cc, 3 h: 0.17 +/- 0.08% ID/cc, n = 9) and [F-18]FAZA (1 h: 1.95 +/- 0.59% ID/cc, 3 h: 0.87 +/- 0.55% ID/cc), whereas T/M ratios were significantly higher for [F-18]FAZDR at 1 h (2.76) compared to [189FAZA (1.69, P < 0.001), 3 h p.i. ratios showed no significant difference. Moreover, [F-18]FAZDR showed an inverse correlation between tracer uptake in carcinomas and oxygen breathing, while muscle tissue uptake was not affected by switching from air to oxygen. Conclusions: First PET imaging results with [F-18]FAZDR showed advantages over [F-18]FAZA regarding higher tumor contrast at earlier time points p.i. Availability of precursor and cold fluoro standard together with high output radiosynthesis will allow for a more detailed quantitative evaluation of [F-18]FAZDR, especially with regard to mechanistic studies whether active transport processes are involved, compared to passive diffusion as observed for [F-18]FAZA. (C) 2016 Elsevier Inc. All rights reserved.