The Synthesis and In Vivo Pharmacokinetics of Fluorinated Arachidonic Acid: Implications for Imaging Neuroinflammation

Journal of Nuclear Medicine

Kishore Kotta¹  Dale Kiesewetter¹  Stanley I. Rapoport¹  Ameer Y. Taha¹  William C. Eckelman¹  Fei Gao¹  Lisa Chang¹  Rama Pichika¹  Yewon Cheon¹ 

关键词: positron emitting tomography (PET);    fluorinated arachidonic acid;    fluoroarachidonic acid;    brain;    phospholipids;    arachidonic acid signaling;    imaging;    neuroinflammation;    excitotoxicity;    biomarker;    Alzheimer’s disease;    cancer;   

DOI  :  10.2967/jnumed.112.105734

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 half-life 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 nonradioactive 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 be worthwhile 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.

【 授权许可】

Unknown