Zinc and copper are essential cations involved in numerous biological processes, and variations in their concentrations can cause diseases such as neurodegenerative diseases, diabetes and cancers. Hence, detection and quantification of these cations are of utmost importance for the early diagnosis of disease. Magnetic resonance imaging (MRI) responsive contrast agents (mainly Lanthanide(+III) complexes), relying on a change in the state of the MRI active part upon interaction with the cation of interest, e.g., switch ON/OFF or vice versa, have been successfully utilized to detect Zn2+ and are now being developed to detect Cu2+. These paramagnetic probes mainly exploit the relaxation-based properties (T1-based contrast agents), but also the paramagnetic induced hyperfine shift properties (paraCEST and parashift probes) of the contrast agents. The challenges encountered going from Zn2+ to Cu2+ detection will be stressed and discussed herein, mainly involving the selectivity of the probes for the cation to detect and their responsivity at physiologically relevant concentrations. Depending on the response mechanism, the use of fast-field cycling MRI seems promising to increase the detection field while keeping a good response. In vivo applications of cation responsive MRI probes are only in their infancy and the recent developments will be described, along with the associated quantification problems. In the case of relaxation agents, the presence of another method of local quantification, e.g., synchrotron X-Ray fluorescence, single-photon emission computed tomography (SPECT) or positron emission tomography (PET) techniques, or 19F MRI is required, each of which has its own advantages and disadvantages.
Keywords: MRI; copper detection; lanthanides; molecular imaging; paraCEST; parashift; quantification; relaxation; responsive contrast agents; zinc detection.