[18F]Fluoro-azomycin-2´-deoxy-β-d-ribofuranoside - A new imaging agent for tumor hypoxia in comparison with [18F]FAZA.
BACKGROUND
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 to18F-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 FXF-Nsynthesizer 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.
Institute of Organic Chemistry, University of Vienna, Vienna, Austria.
Anna
A
Schweifer
Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany.
Florian
F
Maier
Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany.
Walter
W
Ehrlichmann
Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany.
Denis
D
Lamparter
Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany; Department of Dermatology, University of Tübingen, Tübingen, Germany.
Manfred
M
Kneilling
Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany.
Bernd J
BJ
Pichler
Institute of Organic Chemistry, University of Vienna, Vienna, Austria.
Friedrich
F
Hammerschmidt
Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany. Electronic address: gerald.reischl@uni-tuebingen.de.
Gerald
G
Reischl
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D051379:Mice; D009593:Nitroimidazoles / Q000737:chemistry / Q000493:pharmacokinetics; D009705:Nucleosides / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D014018:Tissue Distribution; D000072258:Tumor Hypoxia
D009593:Nitroimidazoles; D009705:Nucleosides; C000618836:fluoroazomycin-2'-deoxyribofuranoside; C498052:fluoroazomycin arabinoside; C006667:azomycin
(18)F PET radiotracers; 2-Nitroimidazole; Small animal imaging; Tumor hypoxia; [(18)F]FAZA