The influence of dynamics on solution state structure is a widely overlooked consideration in chemistry. Variations in Gd3+ chelate hydration with changing coordination geometry and dissociative water exchange kinetics substantially impact the effectiveness (or relaxivity) of mono-hydrated Gd3+ chelates as T1-shortening contrast agents for MRI. Theory shows that relaxivity is highly dependent upon the Gd3+-water proton distance (rGdH) and yet this distance is almost never considered as a variable in assessing the relaxivity of a Gd3+ chelate as a potential contrast agent. The consequence of this omission can be seen when considering the relaxivity of isomeric Gd3+ chelates that exhibit different dissociative water exchange kinetics. The results described herein show that the relaxivity of a chelate with ‘optimal’ dissociative water exchange kinetics is actually lower than that of an isomeric chelate with ‘sub-optimal’ dissociative water exchange. When the rate of molecular tumbling of these chelates is slowed, an approach that has long been understood to increase relaxivity, the observed difference in relaxivity is increased with the more rapidly exchanging (‘optimal’) chelate exhibiting lower relaxivity than the ‘sub-optimally’ exchanging isomer. The difference between the chelates arises from a non-field dependent parameter: either the hydration number (q) or rGdH. For solution state Gd3+ chelates, changes in the values of q and rGdH are indistinguishable. These parametric expressions simply describe the hydration state of the chelate – i.e. the number and position of closely associating water molecules. The hydration state (q/rGdH6) of a chelate is intrinsically linked to its dissociative water exchange rate kex and the interrelation of these parameters must be considered when examining the relaxivity of Gd3+ chelates. The data presented herein indicates that the changes in the hydration parameter (q/rGdH6) associated with changing dissociative water exchange kinetics has a profound effect on relaxivity and suggest that achieving the highest relaxivities in monohydrated Gd3+ chelates is more complicated than simply “optimizing” dissociative water exchange kinetics.

The current trend in magnetic resonance imaging (MRI) is towards higher external magnetic field strengths (B0) to take advantage of increased sensitivity and signal to noise ratio (SNR). Unfortunately, as B0 increases the effectiveness (relaxivity) of clinical gadolinium (Gd 3+)-based contrast agents (CAs) administered to enhance image contrast is significantly reduced. Excellent soft tissue contrast can be generated with current agents despite their non-optimum relaxivities but necessitates large doses. The limits of detection of a CA at high B0 fields can be lowered by recovering the lost relaxivity and is a prerequisite to the goal of molecular imaging in which CAs are bound to biomarkers of pathology that exist at very low concentrations. Traditional methods for increasing the detectability of CAs have focused on optimizing critical parameters identified from the Solomon-Bloembergen-Morgan (SBM) theory that affect relaxivity. Gains in relaxivity with these methods to date have been modest and are far from the theoretical maximum possible. Although researchers continue to investigate novel complexes that provide improved relaxivities, any such complex would require a lengthy and costly approval process with the U.S. Food and Drug Administration (FDA). Therefore, a method that affords improved relaxivities of current clinically approved CAs, particularly at high B0 fields, that could be adopted into clinical practice rapidly, is of great interest. Spin locking is a nuclear magnetic resonance (NMR) technique that was introduced for imaging in 1985, but has received very little attention in combination with Gd 3+-based CAs. The technique employs a low power long duration radiofrequency (RF) pulse (B1) I would like to take this opportunity to thank the following: Prof. Mark Woods for all his support, encouragement and assistance throughout the course of this research.