Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, Mendeleev Building, B-7000 Mons, Belgium.
Contrast Media Mol Imaging. 2011 Jul-Aug;6(4):229-35. doi: 10.1002/cmmi.422. Epub 2010 Dec 29.
Various blood pool contrast agents (CAs), characterized by intravascular distribution, have been developed to assist contrast enhanced magnetic resonance angiography (MRA). Among these CAs, the DTPA derivatives conjugated to synthetic polypeptides, such as polylysine, represent attractive candidates for blood pool imaging. However, due to the presence of charged residues located on their backbone, these agents are retained in the kidneys and this compromises their long blood half-life. In order to overcome this major drawback of the polylysine compounds, two new low-molecular-weight CAs were synthesized in the present work by conjugating four or six 1-p-isothiocyanatobenzyl-DTPA moieties to tri- or penta-Lys peptides [(Gd-DTPA)(4) Lys(3) and (Gd-DTPA)(6) Lys(5)], respectively. All the -NH(2) groups of Lys were thus blocked by covalent conjugation to DTPA. The stability and relaxometric properties of these compounds, as well as their pharmacokinetic and biodistribution characteristics, were then evaluated. The half-life in blood of these new polylysine derivatives, as determined in rats, is twofold longer than that of Gd-DTPA. The compounds could thus be optimal blood pool markers for MRA, which typically uses fast acquisition times. The absence of positive molecular charge did not limit their retention in kidneys 2 h after administration. On the other hand, (Gd-DTPA)(4) Lys(3) is retained in kidneys to a lesser extent than (Gd-DTPA)(6) Lys(5) . Their moderate retention in blood and their higher stability and relaxivity in comparison with Gd-DTPA highlight these polylysine derivatives as optimal compared with previously developed polylysine compounds.
各种血池对比剂（CAs），其特征为血管内分布，已被开发出来以协助对比增强磁共振血管造影（MRA）。在这些 CA 中，与合成多肽（如聚赖氨酸）偶联的 DTPA 衍生物代表了血池成像的有吸引力的候选物。然而，由于其骨架上存在带电荷的残基，这些试剂被保留在肾脏中，这损害了它们的长血液半衰期。为了克服聚赖氨酸化合物的这个主要缺点，本工作通过将四个或六个 1-异硫氰酸根苯甲基-DTPA 部分偶联到三或五聚赖氨酸肽[（Gd-DTPA）（4）Lys（3）和（Gd-DTPA）（6）Lys（5）]上，合成了两种新的低分子量 CA。因此，Lys 的所有-NH2 基团都通过与 DTPA 的共价偶联而被封闭。然后评估了这些化合物的稳定性和弛豫性能，以及它们的药代动力学和生物分布特征。这些新的聚赖氨酸衍生物在大鼠中的半衰期比 Gd-DTPA 长两倍，这表明它们是 MRA 的最佳血池标志物，MRA 通常使用快速采集时间。缺乏正分子电荷并没有限制它们在给药后 2 小时内保留在肾脏中。另一方面，（Gd-DTPA）（4）Lys（3）在肾脏中的保留程度低于（Gd-DTPA）（6）Lys（5）。与 Gd-DTPA 相比，它们在血液中的适度保留以及更高的稳定性和弛豫率突出了这些聚赖氨酸衍生物是优于先前开发的聚赖氨酸化合物的最佳选择。
