MRI relaxation agents based on transition metals

Today, all contrast agents for clinical Magnetic Resonance Imaging (MRI) are gadolinium-based complexes. Following the safety issues raised about gadolinium over the past decade, the scientific community turned its attention to other paramagnetic metal ion alternatives for the development of contrast agents which could provide a better safety profile and biocompatibility. The most obvious choices are high spin Mn2+ (S = 5/2) and Mn3+ (S = 2), and high spin Fe2+ (S = 2) and Fe3+ (S = 5/2). Both manganese and iron are essential elements which alleviates the toxicity concerns related to the use of their complexes as exogenous imaging probes. Mn2+ is an excellent nuclear relaxation probe and is the most promising alternative to replace Gd3+ in contrast agents for MRI. Nevertheless, the stable and inert complexation of Mn2+ is difficult due to its small size, labile nature and the lack of ligand field stabilization energy. Moreover, the complexes need to contain inner sphere water to maintain good relaxivity, which altogether poses a challenge in the ligand design. In the last decade, a large body of data has been gathered including linear and macrocyclic complexes as well as cage molecules which now allow to establish relationships between the structure of the Mn2+ complexes and their stability, inertness and relaxation properties, and this constitutes the basis for a rational design of more stable and efficient probes. High spin Mn3+ is also a good relaxation agent and Mn3+ complexes, in particular porphyrins, have been investigated as MRI probes. Iron complexes have been much less explored, but very recent findings on Fe3+ chelates suggest their great potential to emerge as a new generation of MRI probes. Chelates of Mn2+/3+ and, to a lesser extent, Fe2+/3+ have been also used to derive smart MRI agents with a specific response to various biomarkers, such as pH, enzymes or redox indicators. Our chapter surveys the spectacular evolution of the chemistry of manganese- and iron-based complexes in relation to MRI, with an increasing number of in vivo validation of the novel probes. This area is another beautiful illustration of how fundamental coordination chemistry contributes to the development of useful tools to explore the living system.