Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd3+ Chelates: Why Faster Is Not Always Better
The authors thank the National Institutes of Health (EB-11687) (MW), Oregon Nanoscience and Microtechnologies Institute (N00014-11-1-0193) (MW), Regione Piemonte (Italy) through the NANO-IGT and Prin 2009 Projects (MB & DL), Portland State University and the Oregon Opportunity for Biomedical Research for financial support of this work
Chelates -- Applications to magnetic resonance imaging, Gadolinium -- Diagnostic use, Contrast-enhanced magnetic resonance imaging, Contrast media (Diagnostic imaging)
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 (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 “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 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 indicate 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.
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Published as: Avedano, S., Botta, M., Haigh, J., Longo, D., and Woods, M. (2013). Coupling fast water exchange to slow molecular tumbling in Gd3+ chelates: why faster is not always better. Inorg. Chem., 2013, 52, 8436-8450.
This is the author’s version of a work that was accepted for publication in Inorganic Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Inorganic Chemistry, 2013, 52, 15, 8436-8450.