Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd³⁺ Chelates: Why Faster Is Not Always Better

Abstract

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.

Aggregation in Amphiphilic Macrocycle-Substituted Gd3+ DOTA-Type Chelates Is Affected by the Regiochemistry of Substitution

“…6 The difference between that study 6 and this is the presence or absence of one methyl group (Chart 1). The chelates examined in the previous study were exclusively corner isomers.…”

“…10 However, our work demonstrated that this is not necessarily the case and that water exchange can quite easily be accelerated beyond the point at which it can afford maximum relaxivity. 6 As part of these studies, we noted that substitution of the macrocyclic ring led to the formation of regioisomeric species in the same coordination geometry. 11−13 We had denoted these two regioisomers as "corner" and "side" isomers, depending on the position of the benzylic substitution ( Figure 1).…”

“…4,5 In this way, it has been possible to definitively evaluate how changes in the chelate structure altered its effectiveness as an MRI contrast agent. 6,7 Previous studies 4−7 have often focused on the difference between the two coordination isomers prevalent for all Gd-DOTA-type chelates (DOTA = 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-1,4,7,10-tetraacetate): the square antiprism (SAP) and twisted square antiprism (TSAP). It is well established that the kinetics of water exchange between coordinated water and the bulk in the TSAP isomer are much faster than those in the SAP isomer.…”

Paramagnetic Phospholipid-Based Micelles Targeting VCAM-1 Receptors for MRI Visualization of Inflammation

“…As it has been reported that the hydration state (expressed by the q/r 6 value) of Gd(III) in macrocyclic conformers with different water exchange rates is inversely related to the τ M value, 31,32 the analysis was performed using r Gd-H values of 3.0 Å and 3.1 Å for species 1 and 2, respectively. 31 The good quality of the data fitting is an indirect proof that the advantages deriving from a fast water exchange rate are partially limited by a reduced hydration state. The result of the analysis is consistent with the presence of two paramagnetic species with a predominance of the complex with a very short water exchange lifetime (species 2).…”

Gd‐TEMDO: Design, Synthesis, and MRI Application

“…[11] Compared to TSAP, a SAP geometry will result in slower water exchange, but surprisingly a faster relaxation. [12] The comparable size of the macrocyclic cavity of DOTA and TEMDO indicates that suitable metal ions will very well fit to form thermodynamically stable chelates. [13] Qualitative assessment of free lanthanide ions with indicator xylenol orange showed that chelating generally occurs for the lanthanides.…”