¹⁸F-AmBF₃-phosphonium cations for myocardial perfusion imaging with positron emission tomography

Objectives Several ¹⁸F-labeled lipophilic phosphonium cations have been developed for myocardial perfusion imaging, but most of them require multistep synthesis and/or suffer from significant in vivo defluorination. Recently, ¹⁸F-¹⁹F isotope exchange on ammoniomethyl-trifluoroborate (AmBF₃) was shown to be a facile radiofluorination strategy, and the resulting ¹⁸F-AmBF₃ conjugates exhibited high in vivo stability. In this study, we synthesized and evaluated two ¹⁸F-AmBF₃-conjugated phosphonium cations as potential myocardial perfusion imaging agents.

Methods Two AmBF₃-conjugated phosphonium cations, Z04026 and Z04059, were each synthesized in 4 steps starting from tris(4-methylphenyl)phosphine and tris(3,5-dimethylphenyl)phosphine, respectively. ¹⁸F-labeling was performed via ¹⁸F-¹⁹F isotope exchange with ¹⁸F-fluoride, and purified by solid-phase extraction. Lipophilicity was measured by shake flask method. Biodistribution and imaging studies were performed in CD-1 mice.

Results ¹⁸F-labeled Z04026 and Z04059 were obtained in 12±4 and 17±4% radiochemical yield with >97% radiochemical purity. LogD_7.4 of ¹⁸F-Z04026 and ¹⁸F-Z04059 were 0.1 and 1.1, respectively. Imaging and biodistribution studies showed rapid clearance of both tracers from blood, and their excretion was via both hepatobiliary and renal pathways. At 1 h p.i., the heart uptake was 0.2±0.1 %ID/g for ¹⁸F-Z04026 and 1.0±0.7 %ID/g for ¹⁸F-Z04059. The heart-to-blood and heart-to-muscle ratios were 1.0±0.2 and 1.5±0.2 for ¹⁸F-Z04026, and 8.3±1.9 and 2.8±0.5 for ¹⁸F-Z04059.

Conclusions More lipophilic ¹⁸F-Z04059 showed higher heart uptake and heart-to-background contrast than ¹⁸F-Z04026. However, zwitterionic AmBF₃ might jeopardise free entry of both tracers into myocardium as their heart uptake values are much lower than those (> 20% ID/g) of previously reported ¹⁸F-labeled phosphonium cations.