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

doi:10.6023/A22050226

化学学报 ›› 2022, Vol. 80 ›› Issue (9): 1250-1255.DOI: 10.6023/A22050226 上一篇下一篇

研究论文

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

孙宏顺^a^,^b^,^*(), 周进^a^,^b, 刘成^a^,^b, 陈旭^a^,^b, 杜怡璟^a^,^b, 李玉龙^a, 蒋蕻^a, 王建强^b, 宋喆^c, 郭成^b^,^*()

a 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
b 南京工业大学化学与分子工程学院南京 211816
c 中国药科大学公用服务平台分析测试中心南京 210009

投稿日期:2022-05-15 发布日期:2022-07-19
通讯作者: 孙宏顺, 郭成
基金资助:
江苏省自然科学基金(BK20181486); 江苏省高校自然科学基金(17KJB320001); 南京科技职业学院重点(NJPI-2022-02); 江苏省青蓝工程资助.

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

Hongshun Sun^a^,^b(), Jin Zhou^a^,^b, Cheng Liu^a^,^b, Xu Chen^a^,^b, Yijing Du^a^,^b, Yulong Li^a, Hong Jiang^a, Jianqiang Wang^b, Zhe Song^c, Cheng Guo^b()

a Targeted MRI Contrast Agents Laboratory of Jiangsu Province, Nanjing Polytechnic Institute, Nanjing 210048, China
b College of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China
c Instrumental Analysis Center of CPU, China Pharmaceutical University, Nanjing 210009, China

Received:2022-05-15 Published:2022-07-19
Contact: Hongshun Sun, Cheng Guo
Supported by:
Natural Science Foundation of Jiangsu Province(BK20181486); Natural Science Foundation of the Jiangsu Higher Education Institutions(17KJB320001); Key Program of Nanjing Polytechnic Institute(NJPI-2022-02); Qing Lan Project of Jiangsu Province.

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摘要/Abstract

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Gd³⁺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r₁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: ethoxybenzyl; 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.

关键词: 磁共振成像, 对比剂, 制备, 肝靶向, 弛豫率, 钆, DOTA-酰肼

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 gadolinium ion deposition in patients. In this work, a class of MRI CAs, which contain lipophilic group such as ethoxy aryl or methoxyphenyl and chelating group of DOTA-hydrazide (DOTAH, DOTA: 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid) for Gd³⁺ ion, were designed and prepared. Two synthetic routes (A and B) were discussed and route A was deemed superior. Eight complexes were prepared by one step in the yield of 60%~76% using Gd-DOTAH as main material. They belong 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 Gd³⁺ 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 r₁ 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 introduction of pyridine, indole ring and methoxyphenyl could make CAs lose their liver-specific performance. However, it is worth noting that the methyl on the imine bond (C=N) is beneficial to the liver-specific performance of CAs. Combined with relaxivities, in vitro and in vivo MR imaging data, the lead compound was screened for Gd-DOTAH-EOPEI (7h).

Key words: magnetic resonance imaging (MRI), contrast agents, preparation, liver-specific, relaxivity, gadolinium, DOTA- hydrazide (DOTAH)

引用此文

孙宏顺, 周进, 刘成, 陈旭, 杜怡璟, 李玉龙, 蒋蕻, 王建强, 宋喆, 郭成. 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[J]. 化学学报, 2022, 80(9): 1250-1255.

Hongshun Sun, Jin Zhou, Cheng Liu, Xu Chen, Yijing Du, Yulong Li, Hong Jiang, Jianqiang Wang, Zhe Song, Cheng Guo. Design, Preparation and Evaluation of a Class of Liver-specific Gadolinium-Based Macrocyclic Magnetic Resonance Contrast Agents[J]. Acta Chimica Sinica, 2022, 80(9): 1250-1255.

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图/表 8

图1. 部分已报道的肝靶向磁共振对比剂

Figure 1. Some reported liver targeting MRI contrast agents

图2. 课题组设计制备的大环含钆类磁共振对比剂

Figure 2. Macrocyclic Gd-based MRI CAs designed and prepared by our team

图3. 合成路线及目标化合物

Figure 3. Synthetic routes and the target complexes

Entry	Complex	r₂/ (L•mmol^-1•s^-1)	r₁/ (L•mmol^-1•s^-1)	r₂/r₁
1	Gd-DOTA^[21]	4.3	3.6	1.19
2	7a	4.4	3.7	1.20
3	7b	6.1	5.1	1.20
4	7c	5.9	4.8	1.22
5	7d	5.4	3.9	1.40
6	7e	5.3	4.4	1.20
7	7f	4.9	4.3	1.13
8	7g	6.0	5.1	1.17
9	7h	6.7	5.4	1.24

表1. 合成化合物的弛豫率数据表(0.5 T, Gd-DOTA为参照)

Table 1. The r1 and r2 values of the synthesized complexes at 0.5 T, Gd-DOTA is as control

图4. 体外磁共振成像伪彩图

Figure 4. Pseudocolor maps of in vitro MR imaging

序号	对比剂	给药前-SNR	增强0 h-SNR	增强3 h-SNR	SNR_{0 h}/SNR_pre	SNR_{3 h}/SNR_pre
1	7a	37.43±3.70	45.78±2.32	38.74±1.28	1.22	1.03
2	7b	37.03±2.55	46.40±2.44	46.64±3.03	1.25	1.26
3	7c	37.04±5.76	44.98±3.75	38.63±2.34	1.21	1.04
4	7d	36.15±4.71	40.22±2.60	39.51±0.47	1.11	1.09
5	7e	37.49±0.85	51.67±1.49	42.46±5.94	1.38	1.13
6	7f	35.60±0.86	49.15±3.95	41.24±0.35	1.38	1.16
7	7g	36.55±0.80	45.55±1.85	46.29±1.46	1.25	1.27
8	7h	34.75±3.06	48.88±1.86	47.09±2.13	1.41	1.36
9	Gd-DOTA	35.63±3.34	44.68±2.36	34.09±1.31	1.25	0.96

表2. 给药前后肝脏信噪比对照表(Gd-DOTA作参照)

Table 2. Comparison of liver SNR pre- and post-injection, Gd-DOTA is as control

图5. 给药前后肝脏磁共振成像对比图

Figure 5. MR imaging comparison of liver at pre- and post-injection

图6. 给药前后肝脏磁共振图像灰度值变化图

Figure 6. Gray-scale value of MR imaging for liver at pre- and post-injection

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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

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