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.
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