Ali M Meser, Woods Mark, Caravan Peter, Opina Ana C L, Spiller Marga, Fettinger James C, Sherry A Dean
Department of Chemistry, University of Texas at Dallas, Richardson, TX 75083, USA.
Chemistry. 2008;14(24):7250-8. doi: 10.1002/chem.200800402.
The design of effective pH responsive MRI contrast agents is a key goal in the development of new diagnostic methods for conditions such as kidney disease and cancer. A key factor determining the effectiveness of an agent is the difference between the relaxivity of the "on" state compared to that of the "off" state. In this paper, we demonstrate that it is possible to improve the pH-responsive action of a low molecular weight agent by conjugating it to a macromolecular construct. The synthesis of a bifunctional pH responsive agent is reported. As part of that synthetic pathway we examine the Ing-Manske reaction, identifying an undesirable by-product and establishing effective conditions for promoting a clean and effective reaction. Reaction of the bifunctional pH responsive agent with a G5-PAMAM dendrimer yielded a product with an average of 96 chelates per dendrimer. The relaxivity of the dendrimer conjugate rises from 10.8 mM(-1) s(-1) (pH 9) to 24.0 mM(-1) s(-1) (pH 6) per Gd(3+) ion. This more than doubles the relaxivity pH response, Deltar(1), of our agent from just 51 % for the original low molecular weight chelate to 122 % for the dendrimer.
设计有效的pH响应性磁共振成像（MRI）造影剂是开发针对肾病和癌症等病症的新诊断方法的关键目标。决定造影剂有效性的一个关键因素是“开启”状态与“关闭”状态的弛豫率之间的差异。在本文中，我们证明通过将低分子量试剂与大分子构建体共轭，可以改善其pH响应作用。本文报道了一种双功能pH响应试剂的合成。作为该合成途径的一部分，我们研究了英格-曼斯克反应，鉴定了一种不良副产物，并确定了促进清洁有效反应的有效条件。双功能pH响应试剂与G5-PAMAM树枝状大分子反应，得到的产物平均每个树枝状大分子有96个螯合物。树枝状大分子共轭物的弛豫率从每个Gd(3+)离子10.8 mM(-1) s(-1)（pH 9）提高到24.0 mM(-1) s(-1)（pH 6）。这使我们试剂的弛豫率pH响应Δr(1)增加了一倍多，从原来低分子量螯合物的51%提高到树枝状大分子的122%。
