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

Abstract

Introduction: Radiolabeled 2-nitroimidazoles (azomycins) are a prominent class of biomarkers for PET imaging of hypoxia. [¹⁸F]Fluoro-azomycin-α-arabinoside ([¹⁸F]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 [¹⁸F]FAZA our objective was to ¹⁸F-radiolabel an azomycin-2´-deoxyriboside with β-configuration ([¹⁸F]FAZDR, [¹⁸F]-β-8) to mimic nucleosides more closely and comparatively evaluate it versus [¹⁸F]FAZA.

Methods: Precursor and cold standards for [¹⁸F]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_F-N synthesizer in DMSO and deprotected with NH₄OH to give [¹⁸F]FAZDR ([¹⁸F]-β-8). [¹⁸F]FAZA or [¹⁸F]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 [¹⁸F]FAZDR, we analyzed biodistribution.

Results: [¹⁸F]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 [¹⁸F]FAZDR (1h p.i.: 0.56±0.22% ID/cc, 3h: 0.17±0.08% ID/cc, n=9) and [¹⁸F]FAZA (1h: 1.95±0.59% ID/cc, 3h: 0.87±0.55% ID/cc), whereas T/M ratios were significantly higher for [¹⁸F]FAZDR at 1h (2.76) compared to [¹⁸F]FAZA (1.69, P<0.001), 3h p.i. ratios showed no significant difference. Moreover, [¹⁸F]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 [¹⁸F]FAZDR showed advantages over [¹⁸F]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 [¹⁸F]FAZDR, especially with regard to mechanistic studies whether active transport processes are involved, compared to passive diffusion as observed for [¹⁸F]FAZA.

Keywords: (18)F PET radiotracers; 2-Nitroimidazole; Small animal imaging; Tumor hypoxia; [(18)F]FAZA.