Expanding the Toolkit of Cation‐Responsive MRI Contrast Agents: From Artificial to Bioinspired Design

Zinc and copper are vital trace metal ions that participate in a wide range of physiological and biochemical pathways. Imbalances in their cellular levels have been linked to several disorders, including neurodegenerative conditions, or various cancers. Consequently, precise detection and quantification of these metal ions are critical for early disease diagnosis. Magnetic resonance imaging (MRI) offers a powerful, noninvasive platform for visualizing such ions through responsive contrast agents, most commonly Ln 3+ ‐based complexes. These agents operate by altering their MRI‐active state when they interact with the target metal ion, typically producing a switch in contrast ( off / on or vice versa ). While numerous agents have been successfully engineered for Zn 2+ sensing, efforts are now expanding toward Cu 2+ detection. Transitioning from Zn 2+ to Cu 2+ sensing, however, introduces new challenges, particularly regarding probe selectivity and sensitivity at physiologically relevant ion concentrations. Here, we compare the approaches, possibilities, and limitations provided by artificially engineered or bioinspired cation‐binding sites appended to an MRI active moiety in terms of selectivity, response, affinity, and in vivo applications.