Sheng H, Liang L, Zhou T L, Jia Y X, Wang T, Yuan L, Han H B
Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijng 100191, China.
Peking University Medical and Health Analysis Center, Beijng 100191, China.
Beijing Da Xue Xue Bao Yi Xue Ban. 2020 Oct 18;52(5):959-963. doi: 10.19723/j.issn.1671-167X.2020.05.028.
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.
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.
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 by H nuclear magnetic resonance, C 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.
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 optical imaging to realize the dual synchronous detection of magneto-optics, so that the detection results of the living magnetic resonance imaging and the 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.
改进钆-[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基]-乙酸配合物光磁双模态分子探针的合成及纯化方法。
以1,4,7,10-四氮杂环十二烷（1）为起始原料，经取代反应、水解反应、偶联反应及与金属的络合反应，合成目标化合物（7），即光磁双模态分子探针。
改进了钆-[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基]-乙酸配合物的合成路线。分别通过取代反应、水解反应、偶联反应及与金属的络合反应合成光磁双模态分子探针。改进后的路线总收率可达34.6%，高于原路线（18.0%）。通过氢核磁共振、碳核磁共振及质谱对这些化合物的结构进行了鉴定。改进后的路线可避免取代反应不可控的缺点，减少杂质生成，使纯化过程更简便，在纯化分离方面，将进样量少、成本高的制备型高效液相色谱改进为进样量多、操作简便的柱色谱。因此，柱色谱的使用更有利于光磁双模态分子探针的大规模生产。
改进后的合成路线提高了反应条件的可控性，使化合物的纯化和分离更简便。同时，改进后的合成路线可显著提高总收率。光磁双模态分子探针可将活体磁共振成像与光学成像相结合，实现磁光双同步检测, 使活体磁共振成像和光学成像的检测结果相互验证。也就是说，这种合成的光磁双模态分子探针将使实验结果更准确可靠。在后续的生物学实验研究中，光磁双模态分子探针可应用于脑结构和功能的相关研究，该探针可用于脑相关疾病如脑肿瘤的研究。静脉给药后，光磁双模态分子探针可在脑肿瘤和脑血管疾病的治疗中发挥重要作用。
