Department of Chemistry, Texas Christian University, Fort Worth, TX 76129, USA.
Bioconjug Chem. 2012 Nov 21;23(11):2291-9. doi: 10.1021/bc300461r. Epub 2012 Oct 22.
Four gadolinium (Gd)-based macromolecular contrast agents, G3-(Gd-DOTA)(24), G5-(Gd-DOTA)(96), G3-(Gd-DTPA)(24), and G5-(Gd-DTPA)(96), were prepared that varied in the size of dendrimer (generation three and five), the type of chelate group (DTPA or DOTA), and the theoretical number of metalated chelates (24 and 96). Synthesis relied on a dichlorotriazine derivatized with a DOTA or DTPA ligand that was incorporated into the dendrimer and ultimately metalated with Gd ions. Paramagnetic characteristics and in vivo pharmacokinetics of all four contrast agents were investigated. The DOTA-containing agents, G3-(Gd-DOTA)(24) and G5-(Gd-DOTA)(96), demonstrated exceptionally high r1 relaxivity values at off-peak magnetic fields. Additionally, G5-(Gd-DOTA)(96) showed increased r1 relaxivity in serum compared to that in PBS, which was consistent with in vivo images. While G3-(Gd-DOTA)(24) and G3-(Gd-DTPA)(24) were rapidly excreted into the urine, G5-(Gd-DOTA)(96) and G5-(Gd-DTPA)(96) did not clear as quickly through the kidneys. Molecular simulation of the DOTA-containing dendrimers suggests that a majority of the metalated ligands are accessible to water. These triazine dendrimer-based MRI contrast agents exhibit several promising features such as high in vivo r1 relaxivity, desirable pharmacokinetics, and well-defined structure.
四种基于钆的高分子对比剂，G3-(Gd-DOTA)(24)、G5-(Gd-DOTA)(96)、G3-(Gd-DTPA)(24)和 G5-(Gd-DTPA)(96)，在树状大分子的尺寸（三代和五代）、螯合剂类型（DTPA 或 DOTA）和理论金属螯合基数（24 和 96）方面有所不同。合成依赖于一种用 DOTA 或 DTPA 配体衍生的二氯三嗪，该配体被整合到树状大分子中，最终用 Gd 离子进行金属化。研究了所有四种对比剂的顺磁特性和体内药代动力学。含 DOTA 的试剂 G3-(Gd-DOTA)(24)和 G5-(Gd-DOTA)(96)在非峰值磁场下表现出极高的 r1 弛豫率值。此外，与 PBS 相比，G5-(Gd-DOTA)(96)在血清中的 r1 弛豫率增加，这与体内图像一致。虽然 G3-(Gd-DOTA)(24)和 G3-(Gd-DTPA)(24)迅速通过尿液排出体外，但 G5-(Gd-DOTA)(96)和 G5-(Gd-DTPA)(96)通过肾脏的清除速度并不快。含 DOTA 的树状大分子的分子模拟表明，大多数金属化配体都可与水接触。这些三嗪树状大分子基 MRI 对比剂具有一些有前途的特性，如高体内 r1 弛豫率、理想的药代动力学和明确的结构。
