一类肝靶向含钆大环磁共振对比剂的设计、制备与性能表征  

Design,Preparation and Evaluation of a Class of Liver-specific Gadolinium-Based Macrocyclic Magnetic Resonance Contrast Agents

作　　者：孙宏顺 周进 刘成 陈旭 杜怡璟 李玉龙 蒋蕻 王建强 宋喆[3] 郭成 Sun Hongshun;Zhou Jin;Liu Cheng;Chen Xu;Du Yijing;Li Yulong;Jiang Hong;Wang Jianqiang;Song Zhe;Guo Cheng(Targeted MRI Contrast Agents Laboratory of Jiangsu Province,Nanjing Polytechnic Institute,Nanjing 210048,China;College of Chemistry and Molecular Engineering,Nanjing Tech University,Nanjing 211816,China;Instrumental Analysis Center of CPU,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]南京科技职业学院江苏省磁共振靶向显像剂工程实验室,南京210048 [2]南京工业大学化学与分子工程学院,南京211816 [3]中国药科大学公用服务平台分析测试中心,南京210009

出　　处：《化学学报》2022年第9期1250-1255,共6页Acta Chimica Sinica

基　　金：江苏省自然科学基金(No.BK20181486);江苏省高校自然科学基金(No.17KJB320001);南京科技职业学院重点(No.NJPI-2022-02);江苏省青蓝工程资助。

摘　　要：肝靶向磁共振对比剂有助于肝细胞癌的早期诊断,目前临床使用的线性对比剂存在导致病人肾源性系统性纤维化和钆离子沉积的风险.本工作设计制备了一类含有乙氧芳基或甲氧苯基亲脂性基团、以DOTA-酰肼(DOTA:1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid)为Gd^(3+)离子螯合基团的大环类磁共振对比剂.0.5 T磁场下测得其纵向弛豫率r^(1)值介于3.7~5.4 L·mmol^(−1)·s^(−1),优于临床使用对比剂Gd-DOTA,弛豫率最高的为对比剂7h(Gd-DOTAH-EOPEI)(EOPEI:1-(4-ethoxyphenyl)ethanimine),略高于临床使用肝靶向对比剂Gd-EOB-DTPA(EOB:ethoxybenzy1;DTPA:diethylenetriaminepentaacetic acid),比我们前期制得的肝靶向磁共振对比剂5d提高了约15%.动物活体体内肝靶向磁共振成像研究显示,所制备对比剂7b、7g和7h具有作为肝靶向磁共振对比剂的应用潜力.结合弛豫率和活体体内成像数据,筛选出了先导化合物7h.Liver-specific magnetic resonance imaging(MRI)contrast agents(CAs)are helpful in the early diagnosis of hepatocellular carcinoma.Linear CAs clinically used are at risk of causing nephrogenic systemic fibrosis(NSF)and gadolin-ium ion deposition in patients.In this work,a class of MRI CAs,which contain lipophilic group such as ethoxy aryl or meth-oxyphenyl and chelating group of DOTA-hydrazide(DOTAH,DOTA:1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid)for Gd^(3+)ion,were designed and prepared.Two synthetic routes(A and B)were discussed and route A was deemed su-perior.Eight complexes were prepared by one step in the yield of 60%~76% using Gd-DOTAH as main material.They be-long to macrocyclic gadolinium-based CAs,and have a lower risk for the development of NSF and gadolinium ion deposition in brain.At the same time,the Gd^(3+)binding neutralized the charges of the three acetic groups of DOTAH,leading to nonionic CAs,which is beneficial to low osmotic pressure.Their longitudinal relaxivities r_(1) were from 3.7 to 5.4 L·mmol^(−1)·s^(−1) at 0.5 T,higher than that of Gd-DOTA(3.6 L·mmol^(−1)·s^(−1)).And the relaxivity of complex 7h(Gd-DOTAH-EOPEI)(EOPEI:1-(4-ethoxyphenyl)ethanimine)was the highest of 5.4 L·mmol^(−1)·s^(−1),which was slightly better than clinically used liver-specific CAs of Gd-EOB-DTPA(5.3 L·mmol^(−1)·s^(−1))(EOB:ethoxybenzyl;DTPA:diethylenetriaminepentaacetic acid)and 5d(4.7 L·mmol^(−1)·s^(−1))we have synthesized before.In vivo liver targeting MRI studies in animals showed that complexes of 7b,7g and 7h belong to liver-specific CAs.Among them,complex 7h was optimized.According to structure-activity relationship analysis,the introduction of ethoxyphenyl could obviously improve the liver targeting property.However,increasing the number of ethoxyl and introducing naphthalene ring could not improve the liver targeting property additionally.The introduc-tion of pyridine,indole ring and methoxyphenyl could make CAs lose their liver-specific performance.However,it is wor

关 键 词：磁共振成像 对比剂 制备 肝靶向 弛豫率 钆 DOTA-酰肼 

分 类 号：TQ421.7[化学工程]