Hypoxia-specific tumor imaging with F-18-fluoroazomycin arabinoside

The study was performed to compare the F-18-labeled nitroimidazole compound fluoroazomycin arabinoside (F-18-FAZA) with the standard hypoxia tracer fluoromisonidazole (F-18-FMISO) in detection of tumor tissue hypoxia and to verify the oxygenation dependency of F-18-FAZA uptake. Methods: Biodistribution of F-18-FAZA was studied at various time points in EMT6 tumor-bearing BALB/c mice and in AR42J and A431 tumor-bearing nude mice and compared with that of F-18-FMISO. The presence of tumor tissue hypoxia was verified in 5 EMT6 and 5 AR42J tumors using an oxygen-sensing needle electrode system. To evaluate the oxygenation dependency of F-18-FAZA uptake, using the Munich prototype animal PET scanner, 2 serial PET scans were performed in 13 A431 tumor-bearing nude mice breathing pure oxygen or room air on 1 d and then selecting the other oxygen breathing condition on the following day. In addition, digital autoradiography was performed with EMT6 tumor-bearing F-18-FAZA-dosed, nude mice breathing either room air (n = 8) or carbogen (n = 9). Results: Tissue partial pressure of oxygen (Po-2) electrode measurements revealed that tumor hypoxia was present under room air breathing in EMT6 (tissue Po-2 = 2.9 +/- 2.6) and AR42J tumors (tissue Po-2 = 0.4 +/- 0.2), which was significantly lower compared with that of reference tissue (tissue Po-2 = 25.8 +/- 6.7 and tissue Po-2 29.0 +/- 3.0 [mean +/- SD], respectively; P < 0.01). In all tumor models, F-18-FAZA displayed significantly higher tumor-to-muscle and tumor-to-blood ratios compared with F-18-FMISO, indicating a faster clearance of F-18-FAZA from normal tissues. In AR42J tumors, F-18-FAZA tumor-to-normal ratios were found to increase overtime. Serial animal F-18-FAZA PET studies showed that the tumor-to-background ratio was significantly higher in animals breathing room air compared with that of animals breathing pure oxygen (7.3 +/- 2.3 vs. 4.2 +/- 1.2, respectively; P < 0.001). Similarly, autoradiography showed significantly higher tumor-to-muscle ratios in mice breathing room air compared with those of animals breathing carbogen (5.3 +/- 0.8 vs. 2.2 +/- 0.8; respectively; P < 0.02). Conclusion: F-18-FAZA shows superior biokinetics and is, thus, a promising PET tracer for the visualization of tumor hypoxia. This study also verified a hypoxia-specific uptake mechanism for F-18-FAZA in murine tumor models.