Rational control of water exchange in Gd3+ complexes

描述(由申请人提供)： 基于GD3的磁共振造影剂目前被广泛应用于临床成像和基础科学成像应用。目前FDA批准的药物是相当安全的，对于大多数应用来说，效果非常好。然而，未来的分子成像磁共振应用将要求试剂的检测极限比GdDTPA2或GdDOTA等低分子试剂所能达到的要高得多。大多数致力于解决这一问题的研究人员试图通过将大量离子连接到树枝状大分子或纳米颗粒等大分子上来提高Gd3的灵敏度，而不考虑限制每个聚合物结合物种的弛豫度的基本原理。设计新的高敏感性试剂的限制因素是每个Gd3*结合部位和散装水之间的水交换，这一特征直到最近还不容易控制。我们现在有了这个基础科学问题的解决方案，我们相信最终可能会对临床医学产生重大影响。我们最近证明了选择性地合成GdDOTA类配合物是可能的，其中的配位几何构型被锁定在允许快速水交换的构象中。这将使我们能够合理地控制水交换率，从而实现水的松弛。R21项目的目的是利用这一独特的机会更好地了解包含不同手性中心的配体的结构、Gd3络合物的配位异构体和水交换之间的关系。从这项研究中获得的见解将为设计新一代用于靶向的高弛豫度磁共振造影剂提供关键。我们希望这些结果将允许我们为该领域的其他研究人员提供能够提供更好的松弛性能的配体，用于这些新试剂的设计。在R33项目中，优化后的螯合物将用于组合文库的开发，目前组合文库已广泛应用于药物开发领域。它们允许在短时间内合成和筛选出大量的化合物库。我们将合成和筛选含有我们优化的螯合物的靶向化合物文库，以努力开发真正的候选化合物作为特定蛋白质的靶向造影剂，例如潜在的抗癌药物靶点人类MDM2。

DESCRIPTION (provided by applicant): Gd3+-based MR contrast agents are now widely used in clinical imaging and in basic science imaging applications. Current FDA approved agents are quite safe and for most applications work extremely well. However, future molecular imaging MR applications will require agents with substantially improved detectability limits above what can be achieved with low molecular weight agents such as GdDTPA2- or GdDOTA. Most investigators working to solve this problem have attempted to improve the sensitivity of Gd3+ by attaching large numbers of ions to a large macromolecule such as a dendrimer or a nanoparticle without regard to the fundamental principles that limit the relaxivity of each polymer bound species. The limiting factor in the design of new high sensitivity agents is water exchange between each Gd3*-bound site and bulk water, a feature that until recently has not been easy to control. We now have a solution to this basic science problem that we believe could eventually have a substantial impact in clinical medicine. We recently demonstrated that it is possible to selectively synthesize GdDOTA-like complexes in which the coordination geometry is "locked" into a conformation that allow fast water exchange. This will allow us to rationally control the water exchange rate and hence the water relaxivity that is attainable. The aim of this R21 project is to capitalize upon this unique opportunity to better understand the relationship between the structure of a ligand containing differing chiral centers, the coordination isomers of the Gd3+ complexes, and water exchange. The insights gained from this study will provide the key to design a new generation of high relaxivity MR contrast agents for targeting purposes. We expect that these results will allow us to offer other researchers in this field access to ligands capable of providing improved relaxation properties for use in the design of these new agents. In the R33 project, the optimized chelate will be adapted for use in the development of combinatorial libraries, now widely used in the field of drug development. They allow enormous libraries of compounds to be synthesized and screened in a short period of time. Libraries of targeted compounds incorporating our optimized chelate will be synthesized and screened in an effort to develop a genuine candidate as a targeted contrast agent for a specific protein, such as human Mdm2, a potential anti-cancer drug target.