Protein Binding to Lanthanide(III) Complexes Can Reduce the Water Exchange Rate at the Lanthanide

Abstract

The GdIII-based magnetic resonance imaging contrast agent MS-325 targets the blood protein serum albumin, resulting in an increased efficacy (relaxivity) as a relaxation agent. MS-325 showed different relaxivities when bound to serum albumin from different species, e.g., r1=30.5 mM-1 s-1 (rabbit) vs 46.3 mM-1 s-1 (human) at 35 degrees C and 0.47 T. To investigate the mechanism for this difference, surrogate complexes were prepared where the GdIII ion was replaced by other LnIII ions. Fluorescence lifetime measurements of the EuIII analogue indicated that the hydration number was q=1 and did not change when bound to either human, rat, rabbit, pig, or dog serum albumin. The YbIII analogue, YbL1, was prepared and characterized by 1H NMR. Line-shape analysis of the paramagnetic-shifted 1H NMR resonances in the presence of increasing amounts of human (HSA) or rabbit (RSA) serum albumin allowed estimation of the transverse relaxation rate, R2, of these resonances for the protein-bound YbL1. The rotational correlation time of YbL1 was calculated from R2, and the Yb-H distance and was tauR=8+/-1 ns when bound to HSA and 13+/-2 ns when bound to RSA. The water exchange rate at the DyIII analogue, DyL1, was determined from variable-temperature R2 measurements at 9.4 T when DyL1 was bound to either HSA or RSA. At 37 degrees C, water exchange at DyL1 was (31+/-5)x10(6) s-1 when bound to HSA but (3.8+/-0.2)x10(6) s-1 when bound to RSA. Slower water exchange upon RSA binding explains the differences in relaxivity observed. The approach of using surrogate lanthanides to identify specific molecular parameters influencing relaxivity is applicable to other protein-targeted GdIII contrast agents.

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

“…The attachment of current commercially available contrast agents such as [Gd (DOTA)] 2-and [Gd(DTPA)] 2-to macromolecular constructs has been extensively studied, and in several cases, enhancements have been observed upon slowing of molecular rotation. [71][72][73][74][75][76][77][78][79] These contrast agents, however, are somewhat restricted because they do not have the optimal water-exchange rates that would lead to large enhancements in relaxivity. The major advantage of these aminocarboxylate-based contrast agents is their high watersolubility.…”

“…The commercial agent Vasovist ® (MS-325) is based on this strategy. [71,76,79] Binding of this contrast agent to HSA increases its circulation time in blood and also slows down its tumbling rate, leading to greater contrast enhancements useful for blood vessel imaging. The advantage of this concept is that less material has to be injected into the patient, while the concern is the thermodynamic stability of the complex (i.e.…”

Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

“…For the other isomer of this compound, no crystals suitable for X-ray diffraction could be obtained. The LIS values of the Yb 3+ analog have been successfully simulated with a structural model obtained from the X-ray analysis [222].…”

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents1

“…Several factors related to the linking strategy (such as the rigidity of the linkers, the interaction of Gd-complexing ligands with protein residues, and the flexibility of the protein region containing the amino acid being modified) may also affect the overall relaxivity values in complex ways. [21][22][23][24] Therefore, detailed studies of the relaxometric properties are needed to determine the influence of these factors.To do this, we report herein a detailed analysis of the NMRD profiles and physical parameters of two viral-capsid based contrast agents. Recently we have described the covalent attachment of HOPO based chelates to either the exterior or the interior surface of bacteriophage MS2 capsids devoid of nucleic acids.…”