title: The synthesis and in vivo evaluation of [18F]PF-9811: a novel PET ligand for imaging brain fatty acid amide hydrolase (FAAH).
abstract: BACKGROUND
  Fatty acid amide hydrolase (FAAH) is responsible for the enzymatic degradation of the fatty acid amide family of signaling lipids, including the endogenous cannabinoid (endocannabinoid) anandamide. The involvement of the endocannabinoid system in pain and other nervous system disorders has made FAAH an attractive target for drug development. Companion molecular imaging probes are needed, however, to assess FAAH inhibition in the nervous system in vivo. We report here the synthesis and in vivo evaluation of [(18)F]PF-9811, a novel PET ligand for non-invasive imaging of FAAH in the brain.
  
  
  METHODS
  The potency and selectivity of unlabeled PF-9811 were determined by activity-based protein profiling (ABPP) both in vitro and in vivo. [(18)F]PF-9811 was synthesized in a 3-step, one-pot reaction sequence, followed by HPLC purification. Biological evaluation was performed by biodistribution and dynamic PET imaging studies in male rats. The specificity of [(18)F]PF-9811 uptake was evaluated by pre-administration of PF-04457845, a potent and selective FAAH inhibitor, 1h prior to radiotracer injection.
  
  
  RESULTS
  Biodistribution studies show good uptake (SUV~0.8 at 90 min) of [(18)F]PF-9811 in rat brain, with significant reduction of the radiotracer in all brain regions (37%-73% at 90 min) in blocking experiments. Dynamic PET imaging experiments in rat confirmed the heterogeneous uptake of [(18)F]PF-9811 in brain regions with high FAAH enzymatic activity, as well as statistically significant reductions in signal following pre-administration of the blocking compound PF-04457845.
  
  
  CONCLUSIONS
  [(18)F]PF-9811 is a promising PET imaging agent for FAAH. Biodistribution and PET imaging experiments show that the tracer has good uptake in brain, regional heterogeneity, and specific binding as determined by blocking experiments with the highly potent and selective FAAH inhibitor, PF-04457845.
authors.affiliation: Pfizer Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Mail Stop 8274-1342, Groton, CT 06340, USA. marc.b.skaddan@pfizer.com
authors.forename: Marc B
authors.initials: MB
authors.lastname: Skaddan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhu
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Zasadny
authors.forename: Richard V
authors.initials: RV
authors.lastname: Coelho
authors.forename: Kyle
authors.initials: K
authors.lastname: Kuszpit
authors.forename: Gwen
authors.initials: G
authors.lastname: Currier
authors.forename: Kuo-Hsien
authors.initials: KH
authors.lastname: Fan
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Beck
authors.forename: Laigao
authors.initials: L
authors.lastname: Chen
authors.forename: Susan E
authors.initials: SE
authors.lastname: Drozda
authors.forename: Gayatri
authors.initials: G
authors.lastname: Balan
authors.forename: Micah
authors.initials: M
authors.lastname: Niphakis
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
authors.forename: Thomas
authors.initials: T
authors.lastname: Bocan
authors.forename: Anabella
authors.initials: A
authors.lastname: Villalobos
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology*; D060326:Chemistry Techniques, Synthetic; D008024:Ligands; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011854:Radiochemistry; D051381:Rats; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D008024:Ligands; D010880:Piperidines; D011724:Pyridazines; D000099252:Fatty Acid Amide Hydrolases; C578183:4-(3-((5-(2-fluoroethoxy)pyridin-2-yl)oxy)benzylidene)-N-(pyridazin-3-yl)piperidine-1-carboxamide