Synthesis and comparative evaluation of four 18F-trifluoroborate derivatives of triphenylphosphonium for myocardial perfusion imaging

1137 Objectives Mitochondria-targeting cationic ions including 18F-labeled phosphonium derivatives have been explored to image myocardial perfusion. However, some of these 18F-labeled phosphonium derivatives suffer from tedious multistep labeling process and/or in vivo defluorination. Recently, 18F-19F isotope exchange on a dimethylammoniomethyl-trifluoroborate (AmBF3) motif was reported to be a facile 18F labeling strategy, and the resulting 18F-AmBF3 derivatives were stable in vivo. Therefore, we synthesized four 18F-labeled AmBF3 derivatives of phosphonium with variable lipophilicity, and evaluated their potential for imaging myocardial perfusion with positron emission tomography (PET). Methods Four AmBF3-conjugated phosphonium cations were each synthesized in 4 steps (coupling of triarylphosphine with dibromide spacer, amination with dimethylamine, formation of quaternary ammonium salt using 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and the final conversion into trifluoroborate). The triarylphosphine were tris(4-methylphenyl)phosphine for Z04026, and tris(3,5-dimethylphenyl)phosphine for Z04059, Z04162 and Z04188, respectively. The spacers were 1,3-propanyl for Z04026 and Z04059, and 4,4’-diphenyl and 1,11-undecanyl for Z04162 and Z04188, respectively. The 18F-labeling was performed via 18F-19F isotope exchange reaction in aqueous solution (pH 2) at 80°C, and purified by HPLC. Lipophilicity was measured by shake flask method. Biodistribution and imaging studies were performed in normal CD-1 mice. Results 18F-labeled Z04026, Z04059, Z04162 and Z04188 were obtained in 10 - 17% non-decay-corrected radiochemical yield with 25.9 - 48.1 GBq/µmol specific activity, and > 96% radiochemical purity. LogD7.4 values of Z04026, Z04059, Z04162 and Z04188 were 0.1, 1.1, 1.9 and 2.5 respectively. Imaging and biodistribution studies showed rapid clearance of all four tracers from blood, and their excretion was via both hepatobiliary and renal pathways. At 1 h p.i., the heart was clearly visualized in PET images by using 18F-Z04059, 18F-Z04162 and 18F-Z04188, but not 18F-Z04026. The heart uptake was 0.1 ± 0.1 %ID/g for 18F-Z04026, 0.7 ± 0.2 %ID/g for 18F-Z04059, 0.8 ± 0.1 %ID/g for 18F-Z04162 and 0.6 ± 0.3 %ID/g for 18F-Z04188. The heart-to-blood and heart-to-muscle ratios were 2.2 ± 1.0 and 0.9 ± 0.3 for 18F-Z04026, 12 ± 4.5 and 2.0 ± 0.5 for 18F-Z04059, 2.1 ± 0.9 and 3.6 ± 0.4 for 18F-Z04162 and 3.4 ± 2.4 and 4.6 ± 2.9 for 18F-Z04188. Conclusions We successfully synthesized four 18F-AmBF3 derivatives of phosphonium, and evaluated their potential for myocardial perfusion imaging. Despite clear visualization of heart using 18F-Z04059, 18F-Z04162 and 18F-Z04188, their heart-to-background contrast ratios were inferior to those reported by using other 18F-labeled phosphonium cations. Therefore, these 18F-labeled AmBF3-conjugated phosphonium cations are not suitable for use for imaging myocardial perfusion with PET.