title: Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging.
abstract: 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 [(18)F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [(18)F]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. [(18)F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [(18)F]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 [(18)F]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 [(18)F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [(18)F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.
authors.affiliation: Department of Radiation Oncology (MaastRO Lab), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands. ludwig.dubois@maastrichtuniversity.nl
authors.forename: Ludwig J
authors.initials: LJ
authors.lastname: Dubois
authors.forename: Natasja G
authors.initials: NG
authors.lastname: Lieuwes
authors.forename: Marco H M
authors.initials: MH
authors.lastname: Janssen
authors.forename: Wenny J M
authors.initials: WJ
authors.lastname: Peeters
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Walsh
authors.forename: Hartmuth C
authors.initials: HC
authors.lastname: Kolb
authors.forename: Michel C
authors.initials: MC
authors.lastname: Ollers
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Guus A M S
authors.initials: GA
authors.lastname: van Dongen
authors.forename: Albert
authors.initials: A
authors.lastname: van der Kogel
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
mesh_terms: D000818:Animals; D015415:Biomarkers; D015687:Cell Hypoxia; D005462:Fluorine Radioisotopes; D007093:Imidazoles; D008297:Male; D009374:Neoplasms, Experimental / Q000378:metabolism*; D009593:Nitroimidazoles / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D051381:Rats; D014230:Triazoles
chemical_list: D015415:Biomarkers; D005462:Fluorine Radioisotopes; C562168:HX4 compound; D007093:Imidazoles; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; D014230:Triazoles; C033815:pimonidazole