Shuting Chen1, Zuoquan Zhao2, Ying Zhang1, Wei Fang2, Jie Lu3, Xianzhong Zhang4. 1. Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China. 2. Department of Nuclear Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences, Beijing 100037, PR China. 3. Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China. Electronic address: ljie74@bnu.edu.cn. 4. Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, PR China. Electronic address: zhangxzh@xmu.edu.cn.
Abstract
INTRODUCTION: 18F-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, [18F]4-(fluoromethyl)benzyltris(4-methoxyphenyl) phosphonium cation (1b), [18F]4-(fluoromethyl)benzyltris(2-methoxyphenyl) phosphonium cation (2b) and [18F]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 18F-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 60min 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 99mTc-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.
INTRODUCTION:18F-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, [18F]4-(fluoromethyl)benzyltris(4-methoxyphenyl) phosphonium cation (1b), [18F]4-(fluoromethyl)benzyltris(2-methoxyphenyl) phosphonium cation (2b) and [18F]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 18F-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 60min 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 99mTc-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.
Authors: Chaitanya A Kulkarni; Brian D Fink; Bettine E Gibbs; Pratik R Chheda; Meng Wu; William I Sivitz; Robert J Kerns Journal: J Med Chem Date: 2021-01-04 Impact factor: 7.446