光磁双模态探针钆-[4,7-双-羧甲基-10-(2-荧光素硫脲乙基)-1,4,7,10-四氮杂环十二烷-1-基]-乙酸络合物合成方法的改进

目的:改进光磁双模态分子探针钆-4,7-双-羧甲基-10-(2-荧光素硫脲乙基)-1,4,7,10-四氮杂环十二烷-1-基]-乙酸络合物(Gd-DO3A-EA-FITC)的合成及纯化方法。方法:1,4,7,10-四氮杂环十二烷(DOTA)经过取代反应、水解反应、偶联反应、与金属络合反应,合成Gd-DO3A-EA-FITC。结果:改进了Gd-DO3A-EA-FITC的合成路线,分别通过取代反应、水解反应、偶联反应、络合反应得到了光磁双模态分子探针,该反应总收率为34.6%,与原路线(18.0%)相比,总收率增加,各化合物通过核磁共振氢谱、核磁共振碳谱和质谱分析法鉴定后结果正确。改进后的路线避免了取代反应不易控制的缺点,且在纯化分离方面,将载样量少、成本高的制备型高效液相色谱纯化改进为载样量多、简便易操作的柱色谱。结论:改进后的路线改善了反应条件的可控性,并且使化合物纯化分离过程变得更加简易,同时使总收率明显提升。光磁双模态探针可同时将活体磁共振成像与离体光学成像相结合,实现光磁双重同步检测,使二者的检测结果相互验证。可将光磁双模态分子探针应用于脑结构及其功能相关研究,并且经静脉途径给药后可以对脑肿瘤进行研究,因此在脑肿瘤和脑血管相关疾病的药物治疗中能够发挥重要的作用。

Improved synthesis process of optical-magnetic bimodal probe of Gd-[4,7-Bis-carboxymethyl-10-(2-fluoresceinthioureaethyl)-1,4,7,10-tetraaza-cyclododec-1-yl]-acetic acid complexes

Objective: To improve the methods to synthesize and purify of optical-magnetic bimodal molecular probe of Gd-4,7-Bis-carboxymethyl-10-(2-fluorescein thioureaethyl)-1,4,7,10-tetraaza-cyclododec-1-yl]-acetic acid complexes. Methods: Target compound (7), optical-magnetic bimodal molecular molecular probe, was synthesized by the use of 1,4,7,10-tetraazacyclododecane (1) as starting material via substitution reaction, hydrolysis reaction, coupling reaction and complexation reaction with metal. Results: The synthetic route of Gd-4,7-Bis-carboxymethyl-10-(2-fluoresceinthioureaethyl)-1,4,7,10-tetraaza-cyclododec-1-yl]-acetic acid complexes was improved. The optical-magnetic bimodal molecular probes were synthesized by substitution reaction, hydrolysis reaction, coupling reaction and complex reaction with metal respectively. For the improved route, the total yield could reach 34.6% which was higher than the original route (18.0%). The structures of those compounds were identified by¹H nuclear magnetic resonance, ¹³C nuclear magnetic resonance, and mass spectrometry. The improved route could avoid the uncontrollable disadvantage of the substitution reaction, this process could reduce the formation of impurities and made the purification process easier, and in the aspect of purification and separation, the preparative high-performance liquid chromatography with less sample loading and high cost was improved to a column chromatography with many sample loads and being easy to operate. Therefore, the use of column chromatography could be more conducive to mass production of the optical-magnetic bimodal molecular molecular probe. Conclusion: The improved synthetic route improves the controllability of the reaction conditions and makes it easier to purify and separate the compounds. At the same time, the improved synthetic route can increase the total yield significantly. The optical-magnetic bimodal molecular probe can combine the living magnetic resonance imaging with the in vitro optical imaging to realize the dual synchronous detection of magneto-optics, so that the detection results of the living magnetic resonance imaging and the in vitro optical imaging are mutually verified. In other words, this synthetic optical-magnetic bimodal molecular probe will make the experimental results more accurate and reliable. In subsequent biological experimental studies, the optical-magnetic bimodal molecular probe can be applied to related research of brain structure and function, and the probe can be used for the brain-related diseases researches, such as brain tumors. after intravenous administration, and thus the optical-magnetic bimodal molecular probe can play an important role in medical treatment of brain tumors and cerebrovascular diseases.