The synthesis and in vivo pharmacokinetics of fluorinated arachidonic acid: implications for imaging neuroinflammation.

Pichika, Rama; Taha, Ameer Y; Gao, Fei; Kotta, Kishore; Cheon, Yewon; Chang, Lisa; Kiesewetter, Dale; Rapoport, Stanley I; Eckelman, William C

UNLABELLED 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. CONCLUSION 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.