Effect of methoxy group position on biological properties of 18F-labeled benzyl triphenylphosphonium cations

Introduction: F-18-labeled phosphonium cations targeting mitochondrial membrane potential would be promising for positron emission tomography (PET) myocardial perfusion imaging (MPI). The purpose of this study was to examine the influence of additional methoxy group and its different positions on myocardium uptake and pharmacokinetics properties of 18F-labeled benzyl triphenylphosphonium cations. Method: In this study, three novel 18F-labeled phosphonium cations, [F-18]4-(fluoromethyl)benzyltris(4-methoxyphenyl) phosphonium cation (1b), [F-18]4-(fluoromethyl)benzyltris(2-methoxyphenyl) phosphonium cation (2b) and [F-18]4-(fluoromethyl)benzyltris(3-methoxyphenyl) phosphonium cation (3b), were efficiently prepared by a One-Pot method starting from the substitution of non-carried-added fluoride-18. Radiotracers were purified by HPLC. Physicochemical properties, in vitro cell uptake assay, in vivo mice biodistribution and rat micro-PET imaging were investigated. Results: Results suggested that the position of methoxy group exhibited significant effect on the biological properties of F-18-labeled benzyl triphenylphosphonium cations. The addition of methoxy group on orth- or meta-position of the radiotracers accelerated the radioactivity clearance from liver. The para-radiotracer had the highest uptake in the heart and other non-targeting organs. According to the biodistribution data, 2b (ortho-) displayed the fastest liver clearance and highest heart-to-background ratios. And its rat micro-PET images at 60 min post-injection revealed a good visualization of heart and favorable heart-to-background contrast. Nevertheless, 2b exhibited a lower initial liver uptake and quicker liver clearance compared with Tc-99m-sestamibi. Conclusion: The ortho- compound (2b) displayed the most favorable biological properties as a potential MPI agent to acquire high contrast images early after injection. (C) 2017 Elsevier Inc. All rights reserved.