Conceptually novel MRI paramagnetic contrast agents (PCAs) will be synthesized, which for the first time will simultaneously provide enhanced relaxivity, encapsulation of the metal ion, reduced toxicity, spectroscopic probes of solution dynamics, and metabolically sensitive redox switches. The premise is that enforced nitroxide-metal interactions will increase the native relaxivities of Gd(III)-PCAs by providing an additional conduit to transfer the magnetic moment of the metal to solvating water. The two new proposed classes of chelates go beyond current design paradigms by incorporating rigid nitroxide moieties into well-defined 3-dimensional scaffolds that fix the position of the nitroxide relative to the metal center. This strategy creates motion sensitive probes uncomplicated by internal segmental or anisotropic motions and will allow for the direct determination of the rotational correlation time and other solution rotational dynamical observables. Thus, the water exchange properties of PCAs will be better managed by providing additional interaction modes. Each new PCA will be subjected to variable temperature multifrequency CW EPR studies and complete lineshape analysis to reveal its solution dynamics. In addition, laser fluorescence dynamics experiments will be performed to provide additional data on these observed relaxivities. Finally, each compound will be evaluated for in vitro toxicity. The unique molecular properties of these agents will deliver a better understanding of the structural features that increase PCA effectiveness in a clinical setting. These agents, by virtue of their potential sensitivity to in vivo oxygen concentrations, will allow for the development of metabolically responsive agents with enhanced MRI sensitivity to hypoxia and provide more easily applied agents diagnostically specific for ischemic disorders. The plan is to develop small, yet discriminating PCAs. The complexes form the structural starting point for the development of advanced materials with higher potency, lower toxicity, and better diagnostic specificity, including targeting of specific tissues and pathologies.
| Tekirian, T L; Merriam, D E; Marshansky, V et al. (2001) Subcellular localization of presenilin 2 endoproteolytic C-terminal fragments. Brain Res Mol Brain Res 96:14-20 |
