From electron spin to relaxivity: a multidisciplinary perspective on first-row transition metal-based MRI probes

Abstract

The electron spin is a key enabler of some of the most advanced current technologies. A prime example is the development of MRI contrast agents, where precisely engineered electron spin properties are utilized to enhance the capabilities of one of the most powerful diagnostic tools in the medical science. Clinically approved contrast agents are based on paramagnetic gadolinium(III) complexes. However, to alleviate health and environmental concerns, as well as for specialized applications, alternatives are sought after. Due to their rich chemistry, abundance and low toxicity first-row paramagnetic transition metal ions are emerging as an appealing alternative. A large experimental effort is needed to engineer the new generation of contrast agents. The primary source of information comes from Nuclear Magnetic Relaxation Dispersion (NMRD) profiles. While fitting these profiles can, in principle, yield all the structural and dynamic parameters that influence relaxation, the underlying theoretical models demonstrate a significant challenge. The parameters affect the NMRD profiles in highly coupled, non-separable ways, meaning that a simple, unconstrained fit often results in a non-unique solution. Consequently, the independent experimental determination of some, and preferably most, of these parameters offers a considerable advantage in obtaining reliable and physically meaningful information. This perspective outlines an integrated approach that exploits Electron Paramagnetic Resonance (EPR) spectroscopy for the accurate determination of key molecular parameters. Specifically, EPR is used to quantify the rotational correlation time, the closest proton–metal distance, and the electron spin density at the proton. This methodology is particularly relevant for contrast agents based on first-row transition metal ions. We discuss the contribution of EPR in a complementary context with well-established techniques such as NMR and DFT.