PRIN 2022 n. P20224R8YZ -Exploring Spin Dynamics of Earth Abundant Transition Metal Ion Complexes as MRI Diagnostic Probes -Finanziamento dell’Unione Europea –NextGenerationEU – missione 4, componente 2, investimento 1.1 - CUP D53D23016730001

The progress and innovation of the EU health industry as well as the development of inclusive and safe health policies rely on the development of breakthrough technologies, which in turn are based on the gain of fundamental knowledge. STARS is a curiosity-driven project aiming at advancing our understanding on the spin dynamics of paramagnetic complexes of earth abundant and essential transition metal ion complexes for the design of new and safer magnetic resonance imaging (MRI) contrast agents. Metal containing contrast agents have contributed to the success of MRI as a diagnostic procedure in biomedicine. At present contrast agents are almost exclusively Gd(III) based chelates and 8% of the Gd market share is absorbed by the manufacture of pharmaceutical products for MRI applications. However, criticalities related to Gd supply risks, as well as concerns on its long-term safety, call for possible alternatives. The overarching objective of STARS is to explore Gd substitutes based on abundant and well biologically tolerated paramagnetic first-row transition-metal ions (TMI) such as Cu(II) and V(IV). We plan to combine advanced electron and nuclear magnetic resonance techniques and computational modelling to provide a new and deep understanding of the factors governing the spin dynamics and the relaxivity of a library of Cu and V chelates under different experimental conditions (pH, redox environment, etc). In addition, their potential as a switchable redox sensing contrast agents will be also investigated, exploiting the redox conversion between paramagnetic (Cu(II) and V(IV)) and diamagnetic (Cu(I) and V(V)) redox states. Building upon the partners’ different and complementary competences, STARS will converge towards the following objectives: (O1): To develop an integrated general Magnetic Resonance approach based on the complementary use of advanced EPR and 1H NMR relaxometric techniques for the characterization of paramagnetic relaxivity. (O2): To understand the mechanism of proton relaxation of V(IV) and Cu(II) complexes, assess the role of contact contributions, optimize water interactions, proton exchange and field strength dependence of electronic relaxation of complexes of differing geometry. (O3): To develop a general methodology to translate the analytical results in new advances of health technologies, including optimization of redox responses for the development of activatable compounds, capable of responding to external stimuli such as pH changes. The results are expected to provide the first comprehensive characterization of the relaxivity properties of V and Cu complexes, developing a new holistic approach for the determination of spin dynamic properties of paramagnetic TMI in solution. This knew knowledge will provide guidelines to tune and engineer the relaxation properties of paramagnetic complexes enabling the replacement of critical elements such as Gd and improving the accuracy of existing diagnostic processes.