title: Automated synthesis and PET evaluation of both enantiomers of [¹⁸F]FMISO.
abstract: BACKGROUND
  [(18)F]FMISO, the widely used positron emission tomography (PET) hypoxia tracer, is a chiral compound clinically used as a racemic mixture. The purpose of this study was to synthesize the individual (R)- and the (S)- enantiomers of [(18)F]FMISO and compare their PET imaging characteristics.
  
  
  METHODS
  The radiosynthesis of enantiopure (R)- and (S)-[(18)F]FMISO was based on Co(salen) (N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt)-mediated opening of enantiopure epoxides with [(18)F]HF. The uptake and clearance of the individual [(18)F]FMISO antipodes were investigated using micro-PET/CT imaging performed on mice bearing FaDu tumors. Image-derived biodistribution was obtained from micro-PET/CT scans performed at 1 and 3 hours post injection (p.i.). In addition, the uptake patterns of each enantiomer were observed using two-hour dynamic micro-PET/CT scans, and the time-activity curves from different organs were compared.
  
  
  RESULTS
  The individual (R)- and (S)-[(18)F]FMISO enantiomers were synthesized in one step with high enantiomeric excess (ee)>99% and radiochemical purity>97% using custom-made automation module. The dynamic micro-PET/CT scanning revealed a faster initial uptake of the (R)-[(18)F]FMISO enantiomer in tumor and muscle tissues, however the difference became progressively smaller with time. The tumor-to-muscle (T/M) and tumor-to-liver (T/L) ratios remained nearly identical for the (R)- and (S)-forms at all time points. The micro-PET/CT imaging at 1 and 3 hours p.i. did not show any significant enantioselective tissue uptake.
  
  
  CONCLUSIONS
  Although the (R)-enantiomer of [(18)F]FMISO demonstrated a somewhat faster initial tumor and muscle uptake no significant enantioselective tissue uptake was observed at later time points. The T/M- and T/L- ratios for the (R)- and (S)-forms were the same within the experimental error at all times. Therefore, the use of enantiopure [(18)F]FMISO is unlikely to present any practical clinical benefit for PET imaging.
authors.affiliation: Hevesy Laboratory, DTU Nutech, Frederiksborgvej 399, Building 202, 4000 Roskilde, Denmark.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Revunov
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
authors.forename: Jesper T
authors.initials: JT
authors.lastname: Jørgensen
authors.affiliation: Hevesy Laboratory, DTU Nutech, Frederiksborgvej 399, Building 202, 4000 Roskilde, Denmark.
authors.forename: Andreas Ingemann
authors.initials: AI
authors.lastname: Jensen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark; Department of Micro- and Nanotechnology, Center for Nanomedicine and Theranostics, DTU, 2800 Lyngby, Denmark.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Hansen
authors.affiliation: Hevesy Laboratory, DTU Nutech, Frederiksborgvej 399, Building 202, 4000 Roskilde, Denmark.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Severin
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark. Electronic address: akjaer@sund.ku.dk.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjær
authors.affiliation: Hevesy Laboratory, DTU Nutech, Frederiksborgvej 399, Building 202, 4000 Roskilde, Denmark. Electronic address: fezh@dtu.dk.
authors.forename: Fedor
authors.initials: F
authors.lastname: Zhuravlev
mesh_terms: D000818:Animals; D001331:Automation; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D005260:Female; D006801:Humans; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D013237:Stereoisomerism; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: C031843:fluoromisonidazole; D008920:Misonidazole
keywords: Hypoxia; PET; Radiofluorination; [(18)F]FMISO; [(18)F]HF