CN102973955A - 一种含三价铝的磁共振成像造影剂 - Google Patents
一种含三价铝的磁共振成像造影剂 Download PDFInfo
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Abstract
本发明公开了一种含三价铝的磁共振成像造影剂。该磁共振成像造影剂配体是通过有机溶剂中的液相反应合成得到的,其与镧系稀土元素1:1形成配合物,该配合物能进一步与三价的铝离子按3:1配位而获得所需配合物。该磁共振成像造影剂具有较高的弛豫效率。本发明的造影剂除用于磁共振成像诊断外,还可用于X-射线CT或γ闪烁成像诊断技术。
Description
技术领域
本发明涉及一种磁共振成像造影剂,具体涉及一种含三价铝的磁共振成像造影剂。
背景技术
磁共振成像(magnetic resonance imaging, MRI)是继X-射线CT之后出现的另一举世公认的医学伟大成就,对医疗实践产生了巨大影响。在临床成像中,为了提高病变部位与正常组织间信号的对比度,超过35%的诊断需要使用磁共振成像造影剂。磁共振成像造影剂是一类能缩短成像时间、提高成像对比度和清晰度、显示组织器官功能状态的诊断用药。目前用于临床磁共振成像诊断的造影剂主要为钆或锰的配合物:Gd-DTPA(Magnevist, 马根维显)、Gd-DOTA(Dotarem, 多它灵)、Mn-DPDP(Teslascan, 泰乐影)、Gd-DTPA-BMA(Omniscan, 欧乃影)、Gd-HP-DO3A(Prohance, 普络显思)、Gd-BOPTA(MultiHance, 莫迪司)等,这些小分子造影剂对大脑和中枢神经***等具有良好的成像效果,但其细胞外分布及较快的肾脏代谢限制了其应用,特别是对体内的一些脏器如肝脏、肾脏的造影效果不够理想,不能满足组织、器官选择性的要求。因此,开发造价低廉、低毒性、弛豫效率高且对特定组织或器官具有选择性或靶向性的造影剂,是目前磁共振成像造影剂的发展方向。
近年来,国内外造影剂研究与开发的主流是对二乙三胺五乙酸(Diethylenetriaminepentaacetic acid,DTPA)和1,4,7,10-四氮杂环十二环-1,4,7,10-四乙酸(1,4,7,10-tetraazacyclododecane-N,N′,N″,N′′′-tetraacetic acid, DOTA)及其衍生物进行化学修饰,制造各种类型的造影剂,其中制备高弛豫效率和对生物体具有选择性及靶向性的磁共振成像造影剂,一直是磁共振成像造影剂研究的主要方向。本发明通过化学合成的方法制备了一种Al-Gd自组装的磁共振成像造影剂,它具有较高的弛豫效率和较好的水溶性。
发明内容
本发明的目的是提供一种含三价铝的磁共振成像造影剂。该磁共振成像造影剂是由5-溴甲基-8-羟基喹啉与1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸(DO3A)反应后形成的配体与三价镧系离子形成1:1的配合物,该配合物进一步与三价铝离子按3:1配位获得所需要的顺磁性金属配合物;该顺磁性金属配合物具有如下结构:
Ln是三价镧系离子。优选的镧系元素的三价离子为:Gd3+、Dy3+或Nd3+。
所述的5-溴甲基-8-羟基喹啉修饰的DO3A的配体具有如下结构:
。
根据八羟基喹啉与三价铝具有很强配位能力的特点,将5-溴甲基-8-羟基喹啉与DO3A反应,所形成的配体DO3A部分能与顺磁性金属离子配位,8-羟基喹啉部分与三价铝离子进一步配位,从而获得水溶性好,弛豫效率高的顺磁性金属配合物磁共振成像造影剂。该磁共振成像造影剂具有较高的弛豫效率。本发明的造影剂除用于磁共振成像诊断外,还可用于X-射线CT或γ闪烁成像诊断技术。
具体实施方式
本发明的目的是通过以下技术方案实施的。
具体实施如下:
步骤1:三-(叔丁氧羰基甲基)-1,4,7,10-四氮杂环十二烷(DO3A-tBu)按文献方法制备。取适量的1,4,7,10-四氮杂环十二烷、碳酸氢钠和溴乙酸叔丁酯于HPLC级别的乙腈中室温搅拌48小时,1,4,7,10-四氮杂环十二烷、碳酸氢钠和溴乙酸叔丁酯的物质量比为1:3.2:3。过滤,滤液蒸干后加入大量***,过滤,不溶物真空干燥得产物。产率40%。结构如下:
步骤2:5-甲基-8-叔丁氧羟基喹啉按文献方法制备。取适量的5-甲基-8-羟基喹啉和二碳酸二叔丁酯溶于正己烷溶液中,加入催化剂量的4-二甲氨基吡啶,5-甲基-8-羟基喹啉和二碳酸二叔丁酯的物质量比为1:1,于室温搅拌48h,滤液旋干,重结晶得产物。产率90%。核磁共振氢谱 (CDCl3, ppm): 8.93 (m, 1H), 8.32 (m, 1H), 7.45 (m, 1H), 7.41 (d, 1H), 7.33 (d, 1H), 2.66 (br, 3H), 1.60 (s, 9H). ESI-MS(m/z): 260(M+H+); 282(M+Na+)。结构如下:
步骤3:5-溴甲基-8-叔丁氧羟基喹啉的制备。取适量的5-甲基-8-叔丁氧羟基喹啉和N-溴代丁二酰亚胺溶于四氯化碳溶液中,加入催化剂量的偶氮二异丁腈,5-甲基-8-叔丁氧羟基喹啉和N-溴代丁二酰亚胺的物质量比为1:1.1,回流4小时,趁热过滤,滤液旋干,经过柱层析分离得产物。产率40%。核磁共振氢谱 (CDCl3, ppm): 8.97 (m, 1H), 8.48 (m, 1H), 7.58 (m, 1H), 7.55 (d, 1H), 7.45 (d, 1H), 4.89 (s 2H), 1.60 (s, 9H). ESI-MS(m/z): 339(M+H+); 361(M+Na+)。 结构如下:
步骤4:5-OL-DO3A-tBu的制备。取等当量的DO3A-tBu和5-溴甲基-8-叔丁氧羟基喹啉于乙腈溶液中,加入适量K2CO3,DO3A-tBu,5-溴甲基-8-叔丁氧羟基喹啉和K2CO3的比例为1:1:5,升温至40℃反应24小时。采用硅胶色谱柱分离技术,用二氯甲烷-甲醇(体积比为25:1)作为洗脱液得到产物5-OL-DO3A-tBu。产率60%。核磁共振氢谱 (CDCl3, ppm): 8.96 (m, 1H), 8.62 (m, 1H), 7.54-7.46 (br, 3H), 3.65-2.76 (br, 24H), 1.60 (s, 9H), 1.49 (s, 27H). ESI-MS(m/z): 672(M+H+); 694 (M+Na+)。 结构如下:
步骤5:配体L的制备。将5-OL-DO3A-tBu溶于三氟乙酸和二氯甲烷混合溶液中,三氟乙酸和二氯甲烷的体积比为1:1,室温搅拌24 小时,除去溶剂后,溶于少量甲醇,加入大量***沉淀,过滤,真空干燥,得到产物,产率80%。核磁共振氢谱 (D2O, ppm): 8.95 (m, 1H), 8.61 (m, 1H), 7.53-7.45 (br, 3H),, 3.62-2.73 (br, 24H)。结构如下:
步骤6:Al(GdL)3的制备:取配体L和GdCl3·6H2O溶于适量蒸馏水中,用1 M NaOH将溶液调至pH为10左右,室温搅拌24h后,用1 M NaOH调溶液pH=6.8,5-OL-DO3A和GdCl3·6H2O的物质量比为1:1;然后逐滴加入AlCl3溶液,5-OL-DO3A和AlCl3的物质量比为3:1,用1 M NaOH维持溶液pH=6.8左右,室温搅拌24小时,蒸干溶剂,溶于甲醇,过滤,滤液浓缩至小体积,加入大量***,过滤,真空干燥,得产物,产率85%。通过ICP测试,Gd:Al的原子个数比为3:1。结构如下:
步骤7:将适量步骤6产物溶于重水中,用反转恢复法于bruker Avance III (400 MHz)测定水分子氢核的弛豫时间(t1), 测得弛豫效率为21.5 mM-1·s-1, 约为目前临床所用造影剂Gd-DTPA的4倍左右。
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US11814369B2 (en) | 2016-11-28 | 2023-11-14 | Bayer Pharma Aktiengesellschaft | High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging |
US11944690B2 (en) | 2018-11-23 | 2024-04-02 | Bayer Aktiengesellschaft | Formulation of contrast media and process of preparation thereof |
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US10137209B2 (en) | 2015-06-04 | 2018-11-27 | Bayer Pharma Aktiengesellschaft | Gadolinium chelate compounds for use in magnetic resonance imaging |
US10722601B2 (en) | 2015-06-04 | 2020-07-28 | Bayer Pharma Aktiengesellschaft | Gadolinium chelate compounds for use in magnetic resonance imaging |
US11491245B2 (en) | 2015-06-04 | 2022-11-08 | Bayer Pharma Aktiengesellschaft | Gadolinium chelate compounds for use in magnetic resonance imaging |
US11814369B2 (en) | 2016-11-28 | 2023-11-14 | Bayer Pharma Aktiengesellschaft | High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging |
US11944690B2 (en) | 2018-11-23 | 2024-04-02 | Bayer Aktiengesellschaft | Formulation of contrast media and process of preparation thereof |
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