Coupling fast water exchange to slow molecular tumbling in Gd³⁺ chelates: Why faster is not always better

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 monohydrated Gd³⁺ chelates as T₁-shortening contrast agents for MRI. Theory shows that relaxivity is highly dependent upon the Gd³⁺-water proton distance (r_GdH), 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 "suboptimal" 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 "suboptimally" exchanging isomer. The difference between the chelates arises from a non-field-dependent parameter: either the hydration number (q) or r_GdH. For solution state Gd³⁺ chelates, changes in the values of q and r_GdH 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/r_GdH⁶) of a chelate is intrinsically linked to its dissociative water exchange rate k_ex, and the interrelation of these parameters must be considered when examining the relaxivity of Gd³⁺ chelates. The data presented herein indicate that the changes in the hydration parameter (q/r _GdH⁶) 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.