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.