Rational control of water exchange in Gd3+ complexes

描述（由申请人提供）： 基于Gd 3+的MR造影剂现在广泛用于临床成像和基础科学成像应用中。目前FDA批准的药物是相当安全的，对于大多数应用程序工作非常好。然而，未来的分子成像MR应用将需要具有显著改善的可检测性极限的试剂，其高于用低分子量试剂如GdDTPA 2-或GdDOTA可以实现的极限。致力于解决这个问题的大多数研究人员都试图通过将大量离子连接到大分子如树枝状聚合物或纳米颗粒上来提高Gd 3+的灵敏度，而不考虑限制每个聚合物结合物质的弛豫率的基本原理。新的高灵敏度试剂设计中的限制因素是每个Gd 3 * 结合位点与本体水之间的水交换，这一特征直到最近还不容易控制。我们现在有了一个解决这个基础科学问题的方法，我们相信它最终会对临床医学产生重大影响。我们最近证明，有可能选择性地合成GdDOTA样复合物，其中的配位几何结构被“锁定”为允许快速水交换的构象。这将使我们能够合理地控制水交换率，从而控制可达到的水弛豫率。这个R21项目的目的是利用这个独特的机会，更好地了解含有不同手性中心的配体结构，Gd 3+配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提供设计新一代高弛豫MR造影剂的靶向目的的关键。我们希望这些结果将使我们能够提供其他研究人员在这一领域获得配体能够提供改进的弛豫性能，用于设计这些新的代理。在R33项目中，优化的螯合物将适用于开发组合文库，目前广泛用于药物开发领域。它们允许在短时间内合成和筛选大量化合物库。将合成并筛选包含我们优化的螯合物的靶向化合物库，以努力开发真正的候选物作为特定蛋白质的靶向造影剂，例如人类Mdm 2，一种潜在的抗癌药物靶标。

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.