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- 14C]AA and with PET in Alzheimer disease patients using [1- 11C]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 halflife of 11C-AA and challenges of routinely synthesizing 11C fatty acids limit their translational utility as PET biomarkers. Methods: As a first step to develop a clinically useful 18F-fluoroarachidonic acid ( 18F-FAA) with a long radioactive half-life of 109.8 min, we report here a high-yield stereoselective synthetic method of non-radioactive 20- 19F-FAA. We tested its in vivo pharmacokinetics by infusing purified nonradioactive 19F-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 19F-FAA into brain phospholipids (ratio of brain 19F-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- 14C]AA (the natural arachidonate) infusion in mice. Conclusion: These results suggest that it would beworthwhile to translate our stereoselective synthetic method for 19F-FAA to synthesize positron-emitting 18F-FAA for human brain AA metabolism in neuroinflammatory disorders such as Alzheimer disease. Copyright © 2012 by the Society of Nuclear Medicine and Molecular Imaging, Inc.