title: Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain.
abstract: BACKGROUND
  Two 7-fluoroimidazobenzodiazepines (AH114726 and GEH120348), analogs of flumazenil, were labeled with fluorine-18 and evaluated as alternative radioligands for in vivo imaging of the GABAA/benzodiazepine receptor by comparing them to [(11)C]flumazenil in rhesus monkey.
  
  
  METHODS
  Radiotracers were prepared from the corresponding nitro-precursors in an automated synthesis module, and primate imaging studies were conducted on a Concorde MicroPET P4 scanner. The brain was imaged for 60 (12 × 5 min frames) or 90 min (18 × 5 min frames), and data was reconstructed using the 3D MAP algorithm. Specificity of [(18)F]AH114726 and [(18)F]GEH120348 was confirmed by displacement studies using unlabeled flumazenil.
  
  
  RESULTS
  [(18)F]GEH120348 and [(18)F]AH114726 were obtained in 13-24% yields (end of synthesis) with high chemical (>95%) and radiochemical (>99%) purities, and high specific activities (2061 ± 985 Ci/mmol). The in vivo pharmacokinetics of [(18)F]AH114726 and [(18)F]GEH120348 were determined in a non-human primate and directly compared with [(11)C]flumazenil. Both fluorine-18 radioligands showed time-dependent regional brain distributions that correlated with the distribution of [(11)C]flumazenil and the known concentrations of GABAA/benzodiazepine receptors in the monkey brain. [(18)F]AH114726 exhibited maximal brain uptake and tissue time-radioactivity curves that were most similar to [(11)C]flumazenil. In contrast, [(18)F]GEH120348 showed higher initial brain uptake but very different pharmacokinetics with continued accumulation of radioactivity into the cortical regions of high GABA/benzodiazepine receptor concentrations and very little clearance from the regions of low receptor densities. Rapid washout of both radiotracers occurred upon treatment with unlabeled flumazenil.
  
  
  CONCLUSIONS
  The ease of the radiochemical synthesis, together with in vivo brain pharmacokinetics most similar to [(11)C]flumazenil, support that [(18)F]AH114726 is a suitable option for imaging the GABAA receptor.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Rodnick
authors.forename: Brian G
authors.initials: BG
authors.lastname: Hockley
authors.forename: Phillip
authors.initials: P
authors.lastname: Sherman
authors.forename: Carole
authors.initials: C
authors.lastname: Quesada
authors.forename: Mark R
authors.initials: MR
authors.lastname: Battle
authors.forename: Alexander
authors.initials: A
authors.lastname: Jackson
authors.forename: Karen E
authors.initials: KE
authors.lastname: Linder
authors.forename: Sven
authors.initials: S
authors.lastname: Macholl
authors.forename: William J
authors.initials: WJ
authors.lastname: Trigg
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D005442:Flumazenil / Q000737:chemistry / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes; D008253:Macaca mulatta; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D011963:Receptors, GABA-A; D005442:Flumazenil
keywords: Benzodiazepine; Neurology; PET; Radiopharmaceutical synthesis
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