From Zn(II) to Cu(II) Detection by MRI Using Metal-Based Probes: Current Progress and Challenges

Abstract

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.

In-cell NMR: Why and how?

“…The insets show the resulting 1 H-water signal observed by MRI. A number of chemical scaffolds have been proposed with the same purpose [135][136][137][138][139][140][141]. These can be used for NMR studies on cells; the final goal is often to obtain probes for functional MRI.…”

“…Other 19 F-labeled, 11 B-labeled or hyperpolarized 13 Clabeled or 129 Xe-cage ion sensors have been designed that can report and distinguish the presence of Zn 2+ and Ca 2+ by NMR, but with few applications in cells up to now [137]. We can also mention that many groups have recently proposed Zn 2+ -activated MRI contrast agents to probe extracellular Zn 2+ in brain or prostate, where it may have amyloidogenic properties or diagnostic potential, respectively [140,141,406,407]. Upon Zn 2+ chelation, these molecules either expose a paramagnetic center or exchangeable protons to the solvent, or show altered chemical shifts of 19 F moieties.…”

Pyridine-Dicarbohydrazone-Based Polyacrylate Hydrogels with Strong Mechanical Property, Tunable/Force-Induced Fluorescence, and Thermal/pH Stimuli Responsiveness

“…According to the previous literature, 38 the Eu-based metal−ligand coordination is weaker than the Znbased one. In addition, Malikidogo et al 39 reported Eu-based probes for detecting Zn 2+ ions, and Wang et al 24 mentioned the competition coordination interactions between Eu 3+ and other metal ions, which inspires us to study the fluorescence responsiveness of the Eu-hydrogel in the presence of other metal ions. Figure 4b displays that other metal ions (Al 3+ , Mn 2+ , Fe 3+ , Zn 2+ , Ni 2+ , Co 2+ , and Cu 2+ ) could compete with Eu 3+ to coordinate with (pyridine-dicarbohydrazone)-based ligand within the hydrogel system.…”

Synthesis and characterization of a stable and inert MnII-based ZnII responsive MRI probe for molecular imaging of glucose stimulated zinc secretion (GSZS)

“…6 In the past, SCAs capable of detecting fluctuations in the concentration of biologically relevant metal ions (Ca II , [7][8][9] Zn II (ref. 10) or Cu II (ref. 11)), bioligands (lactate, carbonate, etc.)…”