A Comparative Study of the Hypoxia PET Tracers [18F] HX4, [18F] FAZA, and [18F] FMISO in a Preclinical Tumor Model

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, [F-18] FMISO, [F-18] FAZA, and [F-18] 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 [F-18] FAZA (4.0 +/- 0.5) and at 3 hours p. i. for [F-18] HX4 (7.2 +/- 0.7), whereas [F-18] 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 [F-18] FMISO (R = 0.86; Dice coefficient = 0.76) and [F-18] HX4 (R = 0.76; Dice coefficient = 0.70), whereas [F-18] FAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both [F-18] HX4 and [F-18] FAZA upon 7% oxygen breathing. Only [F-18] 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. (C) 2015 Elsevier Inc.