(62f) Towards Molecular Design of MRI Contrast Agents to Improve NMR Relaxivity and Chemical Stability Using Classical and Quantum Modeling

In Magnetic Resonance Imaging (MRI), the nuclear magnetic resonance (NMR) relaxation of water protons is used to examine bodily tissues. To aid this process, Gadolinium-based contrast agents (GBCAs) are used to enhance image contrast by reducing water proton relaxation time. However, the molecular-scale processes in NMR and MRI are poorly understood, and the modeling and interpretation of the physics of relaxation still rely on severe assumptions. Further complicating the matter, concerns arise from the release of Gadolinium(III) ions in the body, linked to renal impairments and bioaccumulation in bones, brain, and kidneys. Thus, evaluating and enhancing the chemical stability of such chelates proves to be crucial for contrast safety. In this work, we employ quantum and classical molecular simulations to provide important molecular insights into NMR relaxivity and chemical stability of MRI contrast agents. We will discuss how the NMR relaxation signal from simulations can be decomposed into contributions from dynamical “molecular modes,” a technique that can prove powerful in building a library of signals to interpret NMR and MRI signals in otherwise hard-to-analyze environments. Our simulation results are corroborated and validated by NMR relaxation dispersion measurements. Further, we will present an approach based on the molecular Quasi-Chemical Theory (m-QCT) to assess the solvation free energies of Gadolinium(III) ion and its chelated complexes, to address chemical stability of contrast agents. Finally, we will discuss results from both simulations and experiments regarding the effects of two osmolytes, urea and TMAO, on the roles of MRI contrast agents. While urea is a well-known denaturant of protein structure, TMAO has a stabilizing effect on protein structures. Our investigations show that such osmolytes can greatly influence the NMR relaxation of GBCAs.