Radiosynthesis of 20-[18F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice

•An increase in brain arachidonic acid (AA) uptake is a marker of calcium-dependent phospholipase A2 activation and neuroinflammation.•A novel translational synthesis approach of 20-[18F]fluoroarachidonic acid ([18F]-FAA) for PET imaging is presented.•[18F]-FAA showed bioequivalent signaling properties to AA in cells.•The brain incorporation coefficient (K*) of [18F]-FAA was estimated via multiple methods in ApoE4 targeted replacement mice using the image derived input function.•The application of [18F]-FAA PET imaging to humans has relevance to identify and guide the effectiveness of treatments focused on neuroinflammation in neurodegenerative diseases. Dysreglulated brain arachidonic acid (AA) metabolism is involved in chronic inflammation and is influenced by apolipoprotein E4 (APOE4) genotype, the strongest genetic risk factor of late-onset Alzheimer's disease (AD). Visualization of AA uptake and distribution in the brain can offer insight into neuroinflammation and AD pathogenesis. Here we present a novel synthesis and radiosynthesis of 20-[18F]fluoroarachidonic acid ([18F]-FAA) for PET imaging using a convergent route and a one-pot, single-purification radiolabeling procedure, and demonstrate its brain uptake in human ApoE4 targeted replacement (ApoE4-TR) mice. By examining p38 phosphorylation in astrocytes, we found that fluorination of AA at the ω-position did not significantly alter its biochemical role in cells. The brain incorporation coefficient (K*) of [18F]-FAA was estimated via multiple methods by using an image-derived input function from the right ventricle of the heart as a proxy of the arterial input function and brain tracer concentrations assessed by dynamic PET-MR imaging. This new synthetic approach should facilitate the practical [18F]-FAA production and allow its translation into clinical use, making investigations of dysregulation of lipid metabolism more feasible in the study of neurodegenerative diseases.