title: The synthesis and in vivo pharmacokinetics of fluorinated arachidonic acid: implications for imaging neuroinflammation.
abstract: Arachidonic acid (AA) is found in high concentrations in brain phospholipids and is released as a second messenger during neurotransmission and much more so during neuroinflammation and excitotoxicity. Upregulated brain AA metabolism associated with neuroinflammation has been imaged in rodents using [1-(14)C]AA and with PET in Alzheimer disease patients using [1-(11)C]AA. Radiotracer brain AA uptake is independent of cerebral blood flow, making it an ideal tracer despite altered brain functional activity. However, the 20.4-min radioactive half-life of (11)C-AA and challenges of routinely synthesizing (11)C fatty acids limit their translational utility as PET biomarkers.
  
  
  METHODS
  As a first step to develop a clinically useful (18)F-fluoroarachidonic acid ((18)F-FAA) with a long radioactive half-life of 109.8 min, we report here a high-yield stereoselective synthetic method of nonradioactive 20-(19)F-FAA. We tested its in vivo pharmacokinetics by infusing purified nonradioactive (19)F-FAA intravenously for 5 min at 2 doses in unanesthetized mice and measured its plasma and brain distribution using gas chromatography-mass spectrometry.
  
  
  RESULTS
  Incorporation coefficients of injected (19)F-FAA into brain phospholipids (ratio of brain (19)F-FAA concentration to plasma input function) were 3- to 29-fold higher for choline glycerophospholipid and phosphatidylinositol than for ethanolamine glycerophospholipid and phosphatidylserine at each of the 2 tested doses. The selectivities and values of incorporation coefficients were comparable to those reported after [1-(14)C]AA (the natural arachidonate) infusion in mice.
  
  
  CONCLUSIONS
  These results suggest that it would be worthwhile to translate our stereoselective synthetic method for (19)F-FAA to synthesize positron-emitting (18)F-FAA for human brain AA metabolism in neuroinflammatory disorders such as Alzheimer disease.
authors.affiliation: Department of Radiology, UCSD Center for Molecular Imaging, University of California San Diego, San Diego, California 92121, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Pichika
authors.forename: Ameer Y
authors.initials: AY
authors.lastname: Taha
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Kishore
authors.initials: K
authors.lastname: Kotta
authors.forename: Yewon
authors.initials: Y
authors.lastname: Cheon
authors.forename: Lisa
authors.initials: L
authors.lastname: Chang
authors.forename: Dale
authors.initials: D
authors.lastname: Kiesewetter
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D060326:Chemistry Techniques, Synthetic; D054879:Halogenation; D007249:Inflammation / Q000175:diagnosis; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D009422:Nervous System Diseases / Q000175:diagnosis*
chemical_list: D002250:Carbon Radioisotopes; D016718:Arachidonic Acid