A comparative study of the hypoxia PET tracers [¹⁸F]HX4, [¹⁸F]FAZA, and [¹⁸F]FMISO in a preclinical tumor model

Int J Radiat Oncol Biol Phys. 2015 Feb 1;91(2):351-9. doi: 10.1016/j.ijrobp.2014.09.045. Epub 2014 Dec 6.


Purpose: 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 and materials: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cell Line, Tumor
  • Computer Simulation
  • Imidazoles* / pharmacokinetics
  • Misonidazole / analogs & derivatives*
  • Misonidazole / pharmacokinetics
  • Models, Biological
  • Nitroimidazoles* / pharmacokinetics
  • Oxygen / metabolism*
  • Positron-Emission Tomography / methods*
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Reproducibility of Results
  • Rhabdomyosarcoma / diagnostic imaging*
  • Rhabdomyosarcoma / metabolism*
  • Rhabdomyosarcoma / pathology
  • Sensitivity and Specificity
  • Triazoles* / pharmacokinetics


  • HX4 compound
  • Imidazoles
  • Nitroimidazoles
  • Radiopharmaceuticals
  • Triazoles
  • fluoromisonidazole
  • fluoroazomycin arabinoside
  • Misonidazole
  • Oxygen