Abstract
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 r1 of the aqueous phase is determined without any adjustable parameters. The MD simulations of r1 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 r1 dispersion by decomposing the NMR dipole–dipole autocorrelation function G(t) 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 r1, 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 r1 compared to the inner-shell water, in contrast to simulations of (nonchelated) gadolinium-aqua where the outer shell contributes only ∼15% of r1. The deviation between simulations and measurements of r1 below clinical MRI frequencies is used to determine the low-frequency electron-spin relaxation time for Gadobutrol, in good agreement with independent studies.
