title: A comparative study of the hypoxia PET tracers [¹⁸F]HX4, [¹⁸F]FAZA, and [¹⁸F]FMISO in a preclinical tumor model.
abstract: OBJECTIVE
  Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 hypoxia PET tracers frequently used in the clinic, [(18)F]FMISO, [(18)F]FAZA, and [(18)F]HX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification.
  
  
  METHODS
  PET/computed tomography (CT) images of rhabdomyosarcoma R1-bearing WAG/Rij rats were acquired at multiple time points post injection (p.i.) with one of the hypoxia tracers. TBR values were calculated, and reproducibility was investigated by voxel-to-voxel analysis, represented as correlation coefficients (R) or Dice similarity coefficient of the high-uptake volume. Tumor oxygen modifications were induced by exposure to either carbogen/nicotinamide treatment or 7% oxygen breathing.
  
  
  RESULTS
  TBR was stabilized and maximal at 2 hours p.i. for [(18)F]FAZA (4.0 ± 0.5) and at 3 hours p.i. for [(18)F]HX4 (7.2 ± 0.7), whereas [(18)F]FMISO showed a constant increasing TBR (9.0 ± 0.8 at 6 hours p.i.). High spatial reproducibility was observed by voxel-to-voxel comparisons and Dice similarity coefficient calculations on the 30% highest uptake volume for both [(18)F]FMISO (R = 0.86; Dice coefficient = 0.76) and [(18)F]HX4 (R = 0.76; Dice coefficient = 0.70), whereas [(18)F]FAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both [(18)F]HX4 and [(18)F]FAZA upon 7% oxygen breathing. Only [(18)F]FMISO uptake was found to be reversible upon exposure to nicotinamide and carbogen.
  
  
  CONCLUSIONS
  This study indicates that each tracer has its own strengths and, depending on the question to be answered, a different tracer can be put forward.
authors.affiliation: Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address: sarah.peeters@maastrichtuniversity.nl.
authors.forename: Sarah G J A
authors.initials: SG
authors.lastname: Peeters
authors.affiliation: Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Catharina M L
authors.initials: CM
authors.lastname: Zegers
authors.affiliation: Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Natasja G
authors.initials: NG
authors.lastname: Lieuwes
authors.affiliation: Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: van Elmpt
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jonas
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Guus A M S
authors.initials: GA
authors.lastname: van Dongen
authors.affiliation: Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Dubois
authors.affiliation: Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003198:Computer Simulation; D007093:Imidazoles / Q000493:pharmacokinetics; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008954:Models, Biological; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D010100:Oxygen / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results; D012208:Rhabdomyosarcoma / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D012680:Sensitivity and Specificity; D014230:Triazoles / Q000493:pharmacokinetics
chemical_list: C562168:HX4 compound; D007093:Imidazoles; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; D014230:Triazoles; C031843:fluoromisonidazole; C498052:fluoroazomycin arabinoside; D008920:Misonidazole; D010100:Oxygen