Woods Mark, Caravan Peter, Geraldes Carlos F G C, Greenfield Matthew T, Kiefer Garry E, Lin Mai, McMillan Kenneth, Prata M Isabel M, Santos Ana C, Sun Xiankai, Wang Jufeng, Zhang Shanrong, Zhao Piyu, Sherry A Dean
Macrocyclics, Dallas, TX, USA.
Invest Radiol. 2008 Dec;43(12):861-70. doi: 10.1097/RLI.0b013e318186531d.
Recent advances in the design of MRI contrast agents have rendered the lanthanide complexes of DOTA-tetraamide ligands of considerable interest, both as responsive MR agents and paramagnetic chemical exchange saturation transfer agents. The potential utility of these complexes for in vivo applications is contingent upon them being well tolerated by the body. The purpose of this study was to examine how the nature of the amide substituent, and in particular its charge, affected the fate of these chelates postinjection.
Complexes of 6 DOTA-tetraamide ligands were prepared in which the nature of the amide substituent was systematically altered. The 6 ligands formed 3 series: a phosphonate series that included tri-cationic, mono-anionic, and poly-anionic complexes; a carboxylate series made up of a tri-cationic complex and a mono-anionic complex; and lastly, a tri-cationic complex with an aromatic amide substituent. These complexes were labeled with an appropriate radioisotope, either Gd or Lu, and the biodistribution profiles in rats recorded 2 hours postinjection.
Biodistribution profiles were initially acquired at low doses to minimize adverse effects. All the complexes studied were found to be excreted primarily through the renal system, with the majority of the dose being found in the urine. None of the complexes exhibited substantial uptake by bone, liver, and spleen, except for a complex with 4 phosphonate groups that exhibited significant bone targeting capabilities. Increasing the dose of each complex to that of a typical MR contrast agent was found to render all 3 tri-cationic complexes studied here acutely toxic. In contrast, no ill effects were observed after administration of similar doses of the corresponding anionic complexes.
The absence of uptake by the liver and spleen indicate that irrespective of the ligand structure and charge, these complexes are not prone to dissociation in vivo. This is in agreement with previously published work that indicates high kinetic inertness for this class of compounds. At low doses, all complexes were well tolerated; however, for applications that require higher doses, the structure and charge of the ligand becomes a fundamentally important parameter. The results reported herein demonstrate the importance of incorporating negatively charged groups on amide substituents if a DOTA-tetraamide complex is to be employed at high doses in vivo.
MRI造影剂设计的最新进展使DOTA - 四酰胺配体的镧系元素配合物备受关注，它们既作为响应性磁共振试剂，又作为顺磁性化学交换饱和转移试剂。这些配合物在体内应用的潜在效用取决于它们能否被机体良好耐受。本研究的目的是考察酰胺取代基的性质，特别是其电荷，如何影响这些螯合物注射后的命运。
制备了6种DOTA - 四酰胺配体的配合物，其中酰胺取代基的性质被系统地改变。这6种配体形成3个系列：一个膦酸酯系列，包括三阳离子、单阴离子和多阴离子配合物；一个羧酸盐系列，由一个三阳离子配合物和一个单阴离子配合物组成；最后，一个带有芳香酰胺取代基的三阳离子配合物。这些配合物用适当的放射性同位素（钆或镥）标记，并在注射后2小时记录大鼠体内的生物分布情况。
最初以低剂量获取生物分布情况以尽量减少不良反应。研究发现，所有研究的配合物主要通过肾脏系统排泄，大部分剂量存在于尿液中。除了一种带有4个膦酸酯基团的配合物表现出显著的骨靶向能力外，没有一种配合物在骨骼、肝脏和脾脏中有大量摄取。将每种配合物的剂量增加到典型MRI造影剂的剂量时，发现这里研究的所有3种三阳离子配合物都具有急性毒性。相比之下，给予类似剂量的相应阴离子配合物后未观察到不良影响。
肝脏和脾脏未摄取表明，无论配体结构和电荷如何，这些配合物在体内不易解离。这与先前发表的表明此类化合物具有高动力学惰性的研究结果一致。在低剂量时，所有配合物都能被良好耐受；然而，对于需要更高剂量的应用，配体的结构和电荷成为一个至关重要的参数。本文报道的结果表明，如果要在体内高剂量使用DOTA - 四酰胺配合物，在酰胺取代基上引入带负电荷的基团非常重要。
