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.

Keywords: MRI; copper detection; lanthanides; molecular imaging; paraCEST; parashift; quantification; relaxation; responsive contrast agents; zinc detection.

Figure 1

(A) Principal microscopic parameters that influence the relaxivity of Gd³⁺-based contrast agents. (B) ParaCEST Ln³⁺ complex: the ParaCEST effect originates from proton exchange between the bulk water and protons on the ligand or on the coordinated water molecules.

Figure 2

Design of cation responsive contrast agents.

Figure 3

Principle of cation detection by τ_R-modulation, achieved by either self-assembly or by protein binding.

Figure 4

Principle of cation detection by q-modulation.

Figure 5

Zinc responsive contrast agents based on GdDTPA-bisamide systems developed by Nagano et al. In green (Δr₁), black (mechanism of response), brown (response to Zn²⁺ (1 eq.) and selectivity).

Figure 6

Metal-based complexes for Zn²⁺ detection: In green (maximum Δr₁), black (mechanism of response), brown (type of Zn²⁺ response and selectivity).

Figure 6

Metal-based complexes for Zn²⁺ detection: In green (maximum Δr₁), black (mechanism of response), brown (type of Zn²⁺ response and selectivity).

Figure 7

Copper responsive MRI contrast agents: In green (maximum Δr₁), black (mechanism of response), brown (type of Cu²⁺ response and selectivity).

Figure 8

Bioinspired zinc finger peptide and principle for zinc detection by Magnetic resonance imaging (MRI): (A) Structure of bioinspired zinc-finger peptide LnLZF2; (B) Representation of the folding of LnLZF2 upon Zn²⁺ binding; (C) T₁-weighted MR images of phantoms containing Zn-free ad Zn-loaded GdLZF2 at 1.5 T. Adapted with permission from Ref [75]; published by The Royal Society of Chemistry, 2018.

Figure 9

ParaCEST MRI contrast agents for zinc detection.

Figure 10

Parashift probe for Zn²⁺ detection.

Figure 11

(A) Chemical structure of TmPFZ-1; (B) Schematic representation of the conformational exchange within TmPFZ-1 upon Zn²⁺ complexation; (C) ¹⁹F MRI images of TmPFZ-1 (4 mM) in the presence of different Zn²⁺ equivalents. Adapted with permission from Ref [81]; published by The Royal Society of Chemistry, 2020.

Figure 12

Three-dimensional T₁-weighted MR images of mouse pancreas pre or post-injection of GdP8 or GdP20 plus glucose (for Zn²⁺ release). Reproduced with permission from Ref [58]; published by American Chemical Society, 2018.

Figure 13

(A) ¹H NMRD profile of GdP19 alone, in the presence of human serum albumin (HSA), and HAS + Zn²⁺; (B) R₁ map obtained at 2.89 T, the nominal field strength of the MRI system; (C) ΔR₁/ΔB₀ map obtained from subtracting R₁ maps at 2.99 T and 2.79 T. Adapted with permission from Ref [55]; published by Wiley-VCH, 2018.

Figure 14

Paramagnetic probe sensitive to Ca²⁺ and used as a cocktail with the corresponding YP38 for Ca²⁺ quantification.