基于钆络合物的MRI/荧光双模式氟离子探针的合成与性能研究

Fluorine element plays an important role in the life process, but will be a serious health risk once excessive intake. Accordingly, the study of rapid detection methods in water and rhigh-quality imaging techniques in vivo for fluoride will providing great theoretic meaning as well as promising application value in the life and medical fields. In this project, a series of MRI/fluorescence dual-mode fluoride probes were designed and synthetized by the introduction of fluorophores into Gd-DO3A moiety. In these probes, Gd3+ center plays not only a bonding site for fluoride but also a MRI output signal unit. One water molecule coordinated to Gd3+ could be selectively replaced by fluoride in the optimum probe molecule. Therefore, the relaxation rate of Gd-DO3A will be changed and an electronic transfer process also occurred spontaneously within the fluorophores in the process of the displacement reaction, realizing the detection and imaging applications of fluoride by MRI/fluorescence methods. A large amount of imaging information with excellent sensitivity, good selectivity and high resolution will be also achieved by combining the fluorescence method with MRI imaging technique, which could be potentially applied in the prevention, diagnosis, treatment and pathogenesis analysis of endemic fluorosis.

鉴于氟的重要生理作用以及过量摄入对人体健康造成的巨大危害，在荧光探针法检测氟离子工作的基础上，开展高质量的活体内氟离子分布成像技术的研究，将在生命科学和医学等领域具有重要的理论意义和应用价值。本项目在造影剂Gd-DO3A上引入特定荧光基团，构筑了一系列新型的MRI/荧光双模式氟离子探针。探针分子中的Gd3+不仅是氟离子的键合位点，还是MRI信号输出单元。通过恰当调节探针的结构，当氟离子与Gd3+中心作用后，通过竞争作用，取代配位的一个水分子，同步引起Gd-DO3A单元弛豫速率的改变和荧光团内电子的迁移，从而实现对氟离子的检测和MRI/荧光双模式成像。通过MRI/荧光双模式成像技术获取的氟离子在活体内的分布影像具有灵敏度高、分辨率强的特点，而且这类成像试剂可有效去除活体内相关分子、离子的干扰，专一性强。本课题的研究将为地方性氟中毒的预防、诊疗及其发病机理分析等提供详细可靠的影像学信息。

MRI/荧光双模式成像可获得活体内多层次、多方位及高分辨、高灵敏的影像学信息，为医学临床诊断提供可靠的数据支持。本项目采用多胺多羧酸类配体的Gd(Ⅲ)配合物为MRI造影剂，以香豆素等染料为荧光单元，构建了一系列MRI/荧光双模式响应的氟离子探针。通过系统的荧光等光谱分析以及高分辨质谱等表征，获得了探针在水介质中识别氟离子的选择性、灵敏度以及MRI/荧光响应机理。结果发现，基于氟离子与Gd(Ⅲ)强的亲和性，氟离子竞争取代配位的荧光基团和（或）水分子，调控荧光单元的电子/电荷迁移以及Gd(Ⅲ)内层配位水分子数，成功实现了MRI/荧光双信号的协同响应。该系列探针具有高特异性、较低的毒性以及高的灵敏度，适用于活体生物内的成像。以裸鼠为动物模型，证明该系列探针可用于活体内氟离子的磁共振成像（MRI），具有一定的生物医学应用潜质。