Chang Su1,2,3, Dongjian Zhang2,3, Na Bao1, Aiyan Ji1,2,3, Yuanbo Feng2,3,4, Li Chen1, Yicheng Ni2,3,4, Jian Zhang5,6, Zhiqi Yin7. 1. Department of Natural Medicinal Chemistry & State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24, Tongjiaxiang, Gulou District, Nanjing, 210009, Jiangsu Province, People's Republic of China. 2. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, People's Republic of China. 3. Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Qixia District, Nanjing, 210028, Jiangsu Province, People's Republic of China. 4. Theragnostic Laboratory, Campus Gasthuisberg, KU Leuven, 3000, Leuven, Belgium. 5. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, People's Republic of China. zjwonderful@hotmail.com. 6. Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Qixia District, Nanjing, 210028, Jiangsu Province, People's Republic of China. zjwonderful@hotmail.com. 7. Department of Natural Medicinal Chemistry & State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24, Tongjiaxiang, Gulou District, Nanjing, 210009, Jiangsu Province, People's Republic of China. cpu-yzq@cpu.edu.cn.
Abstract
PURPOSE: Identifying necrotic myocardium in ischemic regions is of great importance for risk stratification and clinical decision-making. However, rapid noninvasive imaging of necrotic myocardium is still challenging. This study sought to evaluate the potential of 1,4-naphthoquinones to rapidly visualize necrotic myocardium and the possible mechanisms of necrosis avidity. PROCEDURES: Six 1,4-naphthoquinones were radiolabeled with iodine-131 and the necrosis avidity was estimated in mouse models with muscular necrosis by gamma counting and autoradiography. The necrotic myocardium imaging property and biodistribution of [131I]naphthazarin (6) were determined in rat models with re-perfused myocardial infarction. A possible mechanism of necrosis avidity was explored by in vitro DNA-binding and in vivo blocking experiments. RESULTS: The radiochemical purities of the six radiotracers were greater than 95 %. The uptakes in necrotic muscles of all six radiotracers were higher than those in viable muscles, and [131I]naphthazarin (6) showed the highest necrotic-to-viable ratio and necrosis-to-blood ratio at all tested time points. The necrotic myocardium could be clearly visualized by single-photon emission computed tomography/x-ray computed tomography (SPECT/CT) using [131I]naphthazarin (6) as early as 3 h post-injection. Post-mortem biodistribution showed the uptake of [131I]naphthazarin (6) in necrotic myocardium was 11.67-fold higher than that in viable myocardium. Absorption spectra and emission spectra suggested naphthazarin (6) could bind to DNA through intercalation. The uptake of [131I]naphthazarin (6) in necrotic muscle could be significantly blocked by excessive ethidium bromide (a typical DNA intercalator) and cold naphthazarin (6) with 63.49 and 71.96 % decline at 3 h post-injection in vivo, respectively. CONCLUSIONS: 1,4-Naphthoquinones retained necrosis avidity and [131I]naphthazarin (6) rapidly visualized necrotic myocardium. The necrosis avidity mechanism of [131I]naphthazarin (6) may be attributed to its binding with exposed DNA in necrotic tissues.
PURPOSE: Identifying necrotic myocardium in ischemic regions is of great importance for risk stratification and clinical decision-making. However, rapid noninvasive imaging of necrotic myocardium is still challenging. This study sought to evaluate the potential of 1,4-naphthoquinones to rapidly visualize necrotic myocardium and the possible mechanisms of necrosis avidity. PROCEDURES: Six 1,4-naphthoquinones were radiolabeled with iodine-131 and the necrosis avidity was estimated in mouse models with muscular necrosis by gamma counting and autoradiography. The necrotic myocardium imaging property and biodistribution of [131I]naphthazarin (6) were determined in rat models with re-perfused myocardial infarction. A possible mechanism of necrosis avidity was explored by in vitro DNA-binding and in vivo blocking experiments. RESULTS: The radiochemical purities of the six radiotracers were greater than 95 %. The uptakes in necrotic muscles of all six radiotracers were higher than those in viable muscles, and [131I]naphthazarin (6) showed the highest necrotic-to-viable ratio and necrosis-to-blood ratio at all tested time points. The necrotic myocardium could be clearly visualized by single-photon emission computed tomography/x-ray computed tomography (SPECT/CT) using [131I]naphthazarin (6) as early as 3 h post-injection. Post-mortem biodistribution showed the uptake of [131I]naphthazarin (6) in necrotic myocardium was 11.67-fold higher than that in viable myocardium. Absorption spectra and emission spectra suggested naphthazarin (6) could bind to DNA through intercalation. The uptake of [131I]naphthazarin (6) in necrotic muscle could be significantly blocked by excessive ethidium bromide (a typical DNA intercalator) and cold naphthazarin (6) with 63.49 and 71.96 % decline at 3 h post-injection in vivo, respectively. CONCLUSIONS:1,4-Naphthoquinones retained necrosis avidity and [131I]naphthazarin (6) rapidly visualized necrotic myocardium. The necrosis avidity mechanism of [131I]naphthazarin (6) may be attributed to its binding with exposed DNA in necrotic tissues.
Entities:
Keywords:
1,4-Naphthoquinones; Blood clearance; DNA intercalation; Necrosis avidity; Necrotic myocardium
Authors: Robert F Menger; Whitney L Stutts; Dhanalakshmi S Anbukumar; John A Bowden; David A Ford; Richard A Yost Journal: Anal Chem Date: 2011-12-22 Impact factor: 6.986