title: In-vivo imaging characteristics of two fluorinated flumazenil radiotracers in the rat.
abstract: OBJECTIVE
  [(11)C]Flumazenil shows promise as a clinical and research PET radiotracer to image changes in GABA(A) central benzodiazepine receptor (cBZR), but its widespread use has been limited by practical limitations of [(11)C]. This study evaluated the imaging characteristics of two fluorinated PET radiotracers in rats in vivo: [(18)F]fluoroflumazenil ([(18)F]FFMZ) and [(18)F]flumazenil ([(18)F]FMZ).
  
  
  METHODS
  PET acquisitions were performed on a small-animal scanner following injection of [(18)F]FFMZ in nine rats and [(18)F]FMZ in eight rats. The following treatments were investigated: (1) injection of the tracer dose, (2) presaturation then injection of the tracer dose, and (3) injection of the tracer dose followed by a displacement injection. Unchanged tracer was measured in plasma and brain structures in four animals 10 and 30 min after injection, and ex-vivo autoradiography was also performed.
  
  
  RESULTS
  For both [(18)F]FFMZ and [(18)F]FMZ maximal brain activity peaked rapidly, and was highest in the hippocampus (1.12+/-0.06 SUV, 1.24+/-0.10 SUV, respectively), and lowest in the pons (1.00+/-0.07 SUV, 1.03+/-0.09 SUV, respectively). By 50 min after injection, maximal uptake for [(18)F]FFMZ and [(18)F]FMZ had decreased in the hippocampus to 18+/-3% and 80+/-1% (p<0.01), respectively. The presaturation and displacement studies showed a higher nonspecific component for [(18)F]FFMZ than for [(18)F]FMZ. Metabolite studies showed that at 30 min only 10% of the signal was from [(18)F]FFMZ in the brain. This nonspecific binding was apparent on autoradiography. In contrast, [(18)F]FMZ accounted for >70% of the signal in the brain, which resulted in well-defined regional binding on autoradiography.
  
  
  CONCLUSIONS
  These results demonstrate that [(18)F]FMZ is a superior radiotracer to [(18)F]FFMZ for in-vivo PET imaging of the GABA(A)/cBZR, having slower metabolism and leading to lower concentrations of metabolites in the brain that results in a substantially better signal-to-noise ratio.
authors.affiliation: Department of Medicine (RMH), University of Melbourne, Royal Parade, Parkville, Victoria, Australia.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dedeurwaerdere
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gregoire
authors.forename: Lucy
authors.initials: L
authors.lastname: Vivash
authors.forename: Peter
authors.initials: P
authors.lastname: Roselt
authors.forename: David
authors.initials: D
authors.lastname: Binns
authors.forename: Christopher
authors.initials: C
authors.lastname: Fookes
authors.forename: Ivan
authors.initials: I
authors.lastname: Greguric
authors.forename: Tien
authors.initials: T
authors.lastname: Pham
authors.forename: Christian
authors.initials: C
authors.lastname: Loc'h
authors.forename: Andrew
authors.initials: A
authors.lastname: Katsifis
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Damian E
authors.initials: DE
authors.lastname: Myers
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism; D005442:Flumazenil / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D008297:Male; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000032:analysis / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: C483765:2'-fluoroflumazenil; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; D011963:Receptors, GABA-A; D005442:Flumazenil