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Hypoxia-Specific Tumor Imaging with ¹⁸F-Fluoroazomycin Arabinoside

¹ Nuclear Medicine Clinic, Technical University of Munich, Munich, Germany
² Radiopharmacy, PET Center, University of Tuebingen, Tuebingen, Germany
³ Department of Nuclear Medicine, Institute H. San Raffaele, Milan, Italy
⁴ Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada

The study was performed to compare the ¹⁸F-labeled nitroimidazole compound fluoroazomycin arabinoside (¹⁸F-FAZA) with the standard hypoxia tracer fluoromisonidazole (¹⁸F-FMISO) in detection of tumor tissue hypoxia and to verify the oxygenation dependency of ¹⁸F-FAZA uptake. Methods: Biodistribution of ¹⁸F-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 ¹⁸F-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 ¹⁸F-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 ¹⁸F-FAZA-dosed, nude mice breathing either room air (n = 8) or carbogen (n = 9). Results: Tissue partial pressure of oxygen (PO₂) electrode measurements revealed that tumor hypoxia was present under room air breathing in EMT6 (tissue PO₂ = 2.9 ± 2.6) and AR42J tumors (tissue PO₂ = 0.4 ± 0.2), which was significantly lower compared with that of reference tissue (tissue PO₂ = 25.8 ± 6.7 and tissue PO₂ = 29.0 ± 3.0 [mean ± SD], respectively; P < 0.01). In all tumor models, ¹⁸F-FAZA displayed significantly higher tumor-to-muscle and tumor-to-blood ratios compared with ¹⁸F-FMISO, indicating a faster clearance of ¹⁸F-FAZA from normal tissues. In AR42J tumors, ¹⁸F-FAZA tumor-to-normal ratios were found to increase over time. Serial animal ¹⁸F-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: ¹⁸F-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 ¹⁸F-FAZA in murine tumor models.

Key Words: tumor hypoxia • ¹⁸F-fluoroazomycin arabinoside • PET tracers • mouse tumor model

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