Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 35; pp. 14620 - 14625
• Main Authors: Dubois, Ludwig J, Lieuwes, Natasja G, Janssen, Marco H. M, Peeters, Wenny J. M, Windhorst, Albert D, Walsh, Joseph C, Kolb, Hartmuth C, Öllers, Michel C, Bussink, Johan, van Dongen, Guus A. M. S, van der Kogel, Albert, Lambin, Philippe
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.08.2011; National Acad Sciences
• Subjects: Animals; Biological Sciences; Biomarkers; Blood; Breathing; Cancer; Cell Hypoxia; Fluorine Radioisotopes; Hypoxia; image analysis; Imaging; Imidazoles; Liver; Male; neoplasms; Neoplasms, Experimental - metabolism; nicotinamide; Nitroimidazoles - pharmacology; Oxygen; patients; Positron emission tomography; Positron-Emission Tomography - methods; Radiopharmaceuticals; Rats; Rodents; therapeutics; Tissues; Triazoles; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1102526108

Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [18F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [18F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [18F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [18F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [18F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [18F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [18F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.