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

Abstract Introduction Radiolabeled 2-nitroimidazoles (azomycins) are a prominent class of biomarkers for PET imaging of hypoxia. [18 F]Fluoro-azomycin- α -arabinoside ([18 F]FAZA) - already in clinical use - may be seen as α-configuration nucleoside, but enters cells only via diffusion and is not transported by cellular nucleoside transporters. To enhance image contrast in comparison to [18 F]FAZA our objective was to18 F-radiolabel an azomycin-2´-deoxyriboside with β -configuration ([18 F]FAZDR, [18 F]- β - 8 ) to mimic nucleosides more closely and comparatively evaluate it versus [18 F]FAZA. Methods Precursor and cold standards for [18 F]FAZDR were synthesized from methyl 2-deoxy-D-ribofuranosides α - and β - 1 in 6 steps yielding precursors α - and β - 5. β - 5 was radiolabeled in a GE TRACERlab FXF-N synthesizer in DMSO and deprotected with NH4 OH to give [18 F]FAZDR ([18 F]- β - 8 ). [18 F]FAZA or [18 F]FAZDR were 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 [18 F]FAZDR, we analyzed biodistribution. Results [18 F]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/μmol. Small animal PET imaging showed a decrease in uptake over time for both [18 F]FAZDR (1 h p. i.: 0.56 ± 0.22% ID/cc, 3 h: 0.17 ± 0.08% ID/cc, n = 9) and [18 F]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 [18 F]FAZDR at 1 h (2.76) compared to [18 F]FAZA (1.69, P < 0.001), 3 h p.i. ratios showed no significant difference. Moreover, [18 F]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 [18 F]FAZDR showed advantages over [18 F]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 [18 F]FAZDR, especially with regard to mechanistic studies whether active transport processes are involved, compared to passive diffusion as observed for [18 F]FAZA.