Introduction: Radiolabeled 2-nitroimidazoles (azomycins) are a prominent class of biomarkers for PET imaging of hypoxia. [F]Fluoro-azomycin-α-arabinoside ([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 [F]FAZA our objective was to F-radiolabel an azomycin-2´-deoxyriboside with β-configuration ([F]FAZDR, [F]-β-8) to mimic nucleosides more closely and comparatively evaluate it versus [F]FAZA.
Methods: Precursor and cold standards for [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 FX synthesizer in DMSO and deprotected with NHOH to give [F]FAZDR ([F]-β-8). [F]FAZA or [F]FAZDR was injected in BALB/c mice bearing CT26 colon carcinoma xenografts, PET scans (10min) were performed after 1, 2 and 3h post injection (p.i.). On a subset of mice injected with [F]FAZDR, we analyzed biodistribution.
Results: [F]FAZDR was obtained in non-corrected yields of 10.9±2.4% (9.1±2.2GBq, n=4) 60min EOB, with radiochemical purity >98% and specific activity >50GBq/μmol. Small animal PET imaging showed a decrease in uptake over time for both [F]FAZDR (1h p.i.: 0.56±0.22% ID/cc, 3h: 0.17±0.08% ID/cc, n=9) and [F]FAZA (1h: 1.95±0.59% ID/cc, 3h: 0.87±0.55% ID/cc), whereas T/M ratios were significantly higher for [F]FAZDR at 1h (2.76) compared to [F]FAZA (1.69, P<0.001), 3h p.i. ratios showed no significant difference. Moreover, [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 [F]FAZDR showed advantages over [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 [F]FAZDR, especially with regard to mechanistic studies whether active transport processes are involved, compared to passive diffusion as observed for [F]FAZA.
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