Zinc Sensing with a Pyridine-Based Lanthanide Contrast Agent: Structural Analysis in Aqueous Solution

Zinc is an important physiological cation, and its misregulation is implicated in various diseases. It is therefore important to be able to image zinc by non-invasive methods such as Magnetic Resonance Imaging (MRI). In this work, we have successfully synthesized a novel Gd³⁺-based complex specifically for Zn²⁺ sensing by MRI. Using a combination of NMR, luminescence, potentiometric, and relaxivity experiments, completed with DFT calculations, we demonstrate that incorporating a short linker between the Zn²⁺ sensing unit and the Gd³⁺ complex leads to unique behavior of the system in the absence of Zn²⁺. A significant increase in efficacy of the system is observed upon Zn²⁺ binding, and importantly, the complex is highly selective for Zn²⁺ relative to other physiological cations. A comprehensive structural study reliably determines the microscopic parameters at the origin of the Zn²⁺ response, primarily an increase in the number of water molecules directly coordinated to Gd³⁺ upon Zn²⁺ binding. Crucially, the system maintains a strong response to Zn²⁺ binding in the presence of Human Serum Albumin, highlighting its potential for biological applications.