Transition metal Parashift and ParaCEST MRI agents: Current progress and challenges

The development of ParaCEST and Parashift agents presents opportunities for MRI molecular imaging agents (rather than simple contrast agents) for mapping physiological/biological/chemical environments. Long-term toxicity concerns and questions over sustainability are steering the MRI contrast agent community towards gadolinium-free alternatives, and thus Parashift and ParaCEST research is turning to d-block chemistry. Macrocyclic coordination chemistry is exploited in the judicious design of Parashift/ParaCEST molecular probes for in vivo imaging, to impart water stability as well as solubility, stabilisation of metal oxidation and spin states with anisotropic magnetic susceptibilities (for large hyperfine shifts and suitable paramagnetic relaxation rate enhancements), and optimised exchange dynamics of labile protons for CEST agents. Whilst the current exogenous transition metal Parashift and ParaCEST agents are still in their infancy, in vitro studies demonstrate their potential for in vivo applications. The development of responsive Parashift/ParaCEST agents is also summarised in this review; the mapping of temperature and pH is possible, whilst the prospect of imaging redox potentials and metal ion concentrations is under investigation with proof-of-concept studies. In vivo imaging with transition metal Parashift and/or ParaCEST probes is yet to be established, but studies with lanthanide-based systems demonstrate the possibilities as the chemistry of this field advances, and the role of endogenous MRI contrast due to paramagnetic metal ions is discussed.