title: Comparison of [18F]-FMISO, [18F]-FAZA and [18F]-HX4 for PET imaging of hypoxia--a simulation study.
abstract: BACKGROUND
  To investigate the effect of hypoxia tracer properties on positron emission tomography (PET) image quality for three tracers [18F]-fluoromisonidazole (FMISO), [18F]-fluoroazomycinarabinoside (FAZA) and [18F]-flortanidazole (HX4), using mathematical simulations based on microscopic tumor tissue sections.
  
  
  METHODS
  Oxygen distribution and tracer binding was mathematically simulated on immunohistochemically stained cross-sections of tumor xenografts. Tracer diffusion properties were determined based on available literature. Blood activity and clearance over a four-hour period post-injection (p.i.) were derived from clinical dynamic PET scans of patients suffering from head and neck or bronchial cancer. Simulations were performed both for average patient blood activities and for individual patients, and image contrast between normoxic and hypoxic tissue areas was determined over this four-hour period p.i.
  
  
  RESULTS
  On average, HX4 showed a six-fold higher clearance than FMISO and an almost three-fold higher clearance than FAZA based on the clinical PET data. The absolute variation in clearance was significantly higher for HX4 than for FMISO (standard deviations of 5.75 *10-5 s-1 vs. 1.55 *10-5 s-1). The absolute tracer activity in these scans at four hours p.i. was highest for FMISO and lowest for HX4. Simulated contrast at four hours p.i. was highest for HX4 (2.39), while FMISO and FAZA were comparable (1.67 and 1.75, respectively). Variations in contrast of 7-11% were observed for each tracer depending on the vascularization patterns of the chosen tissue. Higher variations in clearance for HX4 resulted in an increased inter-patient variance in simulated contrast at four hours p.i.
  
  
  CONCLUSIONS
  In line with recent experimental and clinical data, the results suggest that HX4 is a promising new tracer that provides high image contrast four hours p.i., though inter-patient variance can be very high. Nevertheless, the widely used tracer FMISO provides a robust and reproducible signal four hours p.i., but with a lower contrast. The simulations revealed tracer clearance to be the key factor in determining image contrast.
authors.affiliation: a Section for Biomedical Physics, Department of Radiation Oncology , University Hospital Tübingen , Tübingen , Germany.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Wack
authors.affiliation: a Section for Biomedical Physics, Department of Radiation Oncology , University Hospital Tübingen , Tübingen , Germany.
authors.forename: David
authors.initials: D
authors.lastname: Mönnich
authors.affiliation: b Department of Radiation Oncology (MAASTRO) , GROW - School for Oncology and Developmental Biology , Maastricht , The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: van Elmpt
authors.affiliation: b Department of Radiation Oncology (MAASTRO) , GROW - School for Oncology and Developmental Biology , Maastricht , The Netherlands.
authors.forename: Catharina M L
authors.initials: CM
authors.lastname: Zegers
authors.affiliation: b Department of Radiation Oncology (MAASTRO) , GROW - School for Oncology and Developmental Biology , Maastricht , The Netherlands.|c Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.
authors.forename: Esther G C
authors.initials: EG
authors.lastname: Troost
authors.affiliation: d Department of Radiation Oncology , University Hospital Tübingen , Tübingen , Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.affiliation: a Section for Biomedical Physics, Department of Radiation Oncology , University Hospital Tübingen , Tübingen , Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Thorwarth
mesh_terms: D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging; D007093:Imidazoles / Q000493:pharmacokinetics*; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008962:Models, Theoretical; D009593:Nitroimidazoles / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014230:Triazoles / Q000493:pharmacokinetics*
chemical_list: C562168:HX4 compound; D007093:Imidazoles; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; D014230:Triazoles; C031843:fluoromisonidazole; C498052:fluoroazomycin arabinoside; D008920:Misonidazole