坏死亲和性MRI对比剂Gd-DO3A-rhein的合成及其靶向性  

Synthesis and necrosis target of necrosis-avid MRI contrast agent Gd-DO3A-rhein

作　　者：卞丽[1] 高萌[1,2] 黄德健[1] 彭飞[1] 张健[1,2] 殷志琦[3] 

机构地区：[1]南京中医药大学第三临床医学院,南京210028 [2]江苏省中医药研究院转化医学实验室,南京210028 [3]中国药科大学天然药物化学教研室,南京210009

出　　处：《中国药科大学学报》2017年第3期282-288,共7页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81473120);常州四药医院药学科研基金资助项目(No.2014YX011)~~

摘　　要：以大黄酸为底物合成磁共振成像(MRI)对比剂并评价其坏死靶向性。经两步酰化和两步脱保护方法得到新的配体10-{[6-(1,8-二羟基蒽醌-3-甲酰氨基)己基]氨基}乙酰基-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸(DO3A-rhein),再与Gd3+配位得到顺磁性对比剂10-{[6-(1,8-二羟基蒽醌-3-甲酰氨基)己基]氨基}乙酰基-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸钆(Gd-DO3A-rhein)。采用大鼠再灌注肝坏死和肌肉坏死模型评价Gd-DO3A-rhein的坏死靶向性,分别在给予GdDO3A-rhein(0.1 mmol/kg)前和给药后0~12 h进行MRI成像,Gd-DOTA作为对照,成像结束后处死大鼠,对坏死组织进行HE和TTC染色验证坏死模型。MRI成像结果表明,在注射Gd-DO3A-rhein(0.1 mmol/kg)后3、12 h,坏死肝信号呈显著增强,坏死肝与正常肝对比度分别为1.61±0.14、2.36±0.20与给药前(1.16±0.10)呈显著性差异(P<0.05),坏死肌肉呈现同样的结果。以上结果说明,该对比剂具有良好的坏死靶向性,具有成像坏死组织的潜力。The purpose of this study was to synthesize and evaluate the necrosis target of MRI contrast agent based on rhein. The novel ligand 10-{[6-（1, 8-dihydroxyanthraquinone-3-carboxamido）hexyl]amino}acetyl-1, 4, 7, 10-tetraazacyclododecan-1, 4, 7-triacetic acid（DO3A-rhein）was synthesized by two-step acylation and two-step deprotection. The paramagnetic contrast agent gadolinium 10-{[6-（1, 8-dihydroxyanthraquinone-3-carboxamido）hexyl]amino} acetyl-1, 4, 7, 10-tetraazacyclododecan-1, 4, 7-triacetate（Gd-DO3A-rhein）was obtained by coordination of Gd3＋ with the synthesized ligand. Its necrosis affinity was evaluated by liver infarction and muscular necrosis on rat models. The MRI was performed before administration of Gd-DO3A-rhein and during 0 h to 12 h after administration of Gd-DO3A-rhein（0. 1 mmol/kg）, respectively, and Gd-DOTA was used as control. After MRI scanning, rats were sacrificed and necrotic tissues were stained using triphenyltetrazolium chloride（TTC）and hematoxylin-eosin（HE）. MRI images of liver infarction and muscular necrosis on rat models showed significantly enhanced signal intensity compared with normal tissues. The contrast ratios of necrotic liver/normal liver were 1. 61±0. 14 and 2. 36±0. 20 at 3 h and 12 h postinjection of Gd-DO3A-rhein（0. 1 mmol/kg）respectively, demonstrating a significant difference compared with pre-administration of Gd-DO3A-rhein（1. 16±0. 10; P〈0. 05）. The same results were obtained from necrotic muscles. These findings suggested that Gd-DO3A-rhein possessed the necrosis target and imaging capability of necrotic tissues.

关 键 词：大黄酸 Gd-DO3A-rhein 坏死靶向性 肝坏死 磁共振成像 

分 类 号：R914[医药卫生—药物化学]