Molecular-Level Insights into the NMR Relaxivity of Gadobutrol Using Quantum and Classical Molecular Simulations

MRI is an indispensable diagnostic tool in modern medicine; however, understanding the molecular-level processes governing NMR relaxation of water in the presence of MRI contrast agents remains a challenge, hindering the molecular-guided development of more effective contrast agents. By using quantum-based polarizable force fields, the first-of-its-kind molecular dynamics (MD) simulations of Gadobutrol are reported where the ¹H NMR longitudinal relaxivity <i>r</i> ₁ of the aqueous phase is determined <i>without any adjustable parameters</i>. The MD simulations of <i>r</i> ₁ dispersion (i.e., frequency dependence) show good agreement with measurements at frequencies of interest in clinical MRI. Importantly, the simulations reveal key insights into the molecular level processes leading to <i>r</i> ₁ dispersion by decomposing the NMR dipole-dipole autocorrelation function <i>G</i>(<i>t</i>) into a discrete set of molecular modes, analogous to the eigenmodes of a quantum harmonic oscillator. The molecular modes reveal important aspects of the underlying mechanisms governing <i>r</i> ₁, such as its multiexponential nature and the importance of the second eigenmodal decay. By simply analyzing the MD trajectories on a parameter-free approach, the Gadobutrol simulations show that the outer-shell water contributes ∼50% of the total relaxivity <i>r</i> ₁ compared to the inner-shell water, in contrast to simulations of (nonchelated) gadolinium-aqua where the outer shell contributes only ∼15% of <i>r</i> ₁. The deviation between simulations and measurements of <i>r</i> ₁ below clinical MRI frequencies is used to determine the low-frequency electron-spin relaxation time for Gadobutrol, in good agreement with independent studies.