This work plan outlines a research program designed systematically to investigate the relationships between paramagnetic contrast agent (PCA) molecular structure and the ability of these agents to enhance water proton spin relaxation in the context of clinical MRI examinations. A detailed understanding of these structure/function relationships in PCAs containing Gd+3 or Mn+2 will assist in the rational design of new contrast agents with tailored properties; through such an approach we already have helped guide the creation of an advanced agent which currently is undergoing clinical trials. Such information is especially necessary, for PCA design because the properties of any agent are the result of a complex set of interactions involving the paramagnetic material, the molecular structure of the chelate, water, and the biological surroundings. The plan outlined here is based upon a methodological foundation which has been developed over the last five years in our laboratory. This approach includes several complementary magnetic resonance techniques, each of which is designed individually to observe one of the key interactions controlling PCA performance. We utilize multi-frequency electron paramagnetic resonance (EPR at 0.5, 1, 3, 9.5, 35, and 95 GHz), 17O NMR, electron spin echo (ESB), and electron-nuclear double resonance (ENDOR) spectroscopies, as well as nuclear magnetic relaxation dispersion (NMRD) measurements, in this protocol. In order to perform certain experiments, we have constructed one-of-a-kind instruments, like the 95 GHz EPR and the 2 - 4 GHz ESE spectrometers. This suite of instruments is unique in the USA, and it affords us special opportunities to make physical measurements that relate PCA structure to individual factors affecting performance (e.g. water access and organization, tumbling rate, zero field splitting, electron spin relaxation). Also unique in the plan is our collaboration with Schering, AG (Berlin, Germany). Schering organic chemists provide us with a wide variety of special PCAs, often synthesized to our specifications. The collaboration has been extremely successful, providing us at all times with a source of precisely characterized, high-purity agents.
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