Design and synthesis of MRI contrast agents and their biological applications

钆离子（Gd^<3+>）络合物通常用作磁共振成像（MRI）造影剂以增强T1加权MR图像中的信号。大多数MRI造影剂主要是具有非特异性生物分布的细胞外试剂。然而，通过对Gd^<3 +>进行适当的配体设计，也有可能开发出具有各种化学性质的Gd^<3 +>配合物。在本研究中，我们开发了一种新的方法，通过使用疏水荧光染料作为细胞通透性增强单元和动脉粥样硬化斑块的靶向部分来获得功能性Gd^<3+>配合物。也就是说，我们已经合成了Gd^<3+>与各种疏水性荧光染料的结合物，并表明这些结合物可以有效地导入细胞。此外，我们还设计并合成了Gd^<3+>配合物和硼二吡咯亚甲基（BDP）衍生物的新型MRI造影剂，并成功地通过MRI显示了ApoE^<-/->小鼠的动脉粥样硬化斑块。因此，疏水荧光染料的缀合似乎是控制Gd^<3+>配合物功能的有效方法，并且应该适用于进一步开发功能性Gd^<3+>基MRI造影剂。

Gadolinium ion (Gd^<3+>) complexes are commonly used as magnetic resonance imaging (MRI) contrast agents to enhance signals in T1-weighted MR images. Most MRI contrast agents are mainly extracellular agents with nonspecific biodistribution. However, it is also possible to develop Gd^<3+> complexes with various chemical properties by means of appropriate ligand design for Gd^<3+>. In this research, we have developed a novel method to achieve functional Gd^<3+> complexes by using hydrophobic fluorescent dyes as a cell-permeability-enhancing unit and a targeting moiety for atherosclerotic plaques. i.e., we have synthesized Gd^<3+> complexes conjugated with various hydrophobic fluorescent dyes, and showed that these conjugates could be introduced efficiently into cells. Moreover, we have designed and synthesized novel MRI contrast agents by combining Gd^<3+> complexes and boron dipyrromethene (BDP) derivatives, and have successfully visualized atherosclerotic plaques of ApoE^<-/-> mice by MRI. Thus, conjugation of hydrophobic fluorescent dyes appears to be an effective approach to control the functions of Gd^<3+> complexes, and should be applicable for further development of functional Gd^<3+>-based MRI contrast agents.