Rational control of water exchange in Gd3+ complexes

Gd3配合物中水交换的合理控制

基本信息

批准号：
6864434
负责人：
MARK WOODS
金额：
$ 13万
依托单位：
MACROCYCLICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2007-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6864434
关键词：
bioimaging /biomedical imaging bioluminescence chelating agents chemical kinetics chemical synthesis contrast media gadolinium ligands magnetic resonance imaging metal complex molecular /cellular imaging protein binding stereoisomer thermodynamics water

项目摘要

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.

描述（由申请人提供）：基于 Gd3+ 的 MR 造影剂现已广泛用于临床成像和基础科学成像应用。目前 FDA 批准的药物非常安全，并且对于大多数应用来说效果非常好。然而，未来的分子成像 MR 应用将需要具有显着改善的可检测性极限的试剂，该极限高于低分子量试剂（例如 GdDTPA2- 或 GdDOTA）所能达到的水平。大多数致力于解决这一问题的研究人员都试图通过将大量离子附着到树枝状聚合物或纳米颗粒等大分子上来提高 Gd3+ 的灵敏度，而不考虑限制每种聚合物结合物质的弛豫率的基本原理。新型高灵敏度试剂设计中的限制因素是每个 Gd3* 结合位点与大量水之间的水交换，这一特征直到最近还不容易控制。我们现在找到了这个基础科学问题的解决方案，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，可以选择性地合成类似 GdDOTA 的复合物，其中配位几何形状被“锁定”到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，从而控制可达到的水弛豫度。 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结构、Gd3+ 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为设计用于靶向目的的新一代高弛豫磁共振造影剂提供关键。我们期望这些结果将使我们能够为该领域的其他研究人员提供能够提供改进的松弛特性的配体，以用于这些新试剂的设计。在R33项目中，优化后的螯合物将适用于组合文库的开发，目前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大量化合物库。我们将合成和筛选包含我们优化的螯合物的靶向化合物库，以开发真正的候选药物作为特定蛋白质（例如潜在抗癌药物靶点人类 Mdm2）的靶向造影剂。