Radiosynthesis of 20-[18F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice. (November 2022)

• Record Type: Journal Article
• Authors: Van Valkenburgh, Juno; Duro, Marlon Vincent V.; Burnham, Erica; Chen, Quan; Wang, Shaowei; Tran, Jenny; Kerman, Bilal E.; Hwang, Sung Hee; Liu, Xiaodan; Sta. Maria, Naomi S.; Zanderigo, Francesca; Croteau, Etienne; Rapoport, Stanley I.; Cunnane, Stephen C.; Jacobs, Russell E.; Yassine, Hussein N.; Chen, Kai
• Is Part Of: Prostaglandins, leukotrienes, and essential fatty acids. Volume 186(2022)
• Publication Date: 2022-11
• Subjects: Arachidonic acid -- Fatty acid -- PET-MR -- Brain imaging -- ApoE4; Lipids -- Periodicals; Unsaturated fatty acids -- Periodicals; Prostaglandins -- Periodicals; Leukotrienes -- Periodicals; Fatty Acids, Unsaturated -- Periodicals; Acides gras insaturés -- Périodiques; Prostaglandines -- Périodiques; Leucotriènes -- Périodiques; Lipides -- Périodiques; 612.01577
• DOI: 10.1016/j.plefa.2022.102510
• Languages: English
• ISSNs: 0952-3278

Abstract

Highlights: 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-[ 18 F]fluoroarachidonic acid ([ 18 F]-FAA) for PET imaging is presented. [ 18 F]-FAA showed bioequivalent signaling properties to AA in cells. The brain incorporation coefficient ( K *) of [ 18 F]-FAA was estimated via multiple methods in ApoE4 targeted replacement mice using the image derived input function. The application of [ 18 F]-FAA PET imaging to humans has relevance to identify and guide the effectiveness of treatments focused on neuroinflammation in neurodegenerative diseases. Abstract: 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-[ 18 F]fluoroarachidonic acid ([ 18 F]-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 [ 18 F]-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 [ 18 F]-FAA production and allow its translation into clinical use, making investigations of dysregulation of lipid metabolism more feasible in the study of neurodegenerative diseases.