Small-Molecule Fe ³⁺ -Based Magnetic Resonance Imaging Probe Enables Noninvasive Imaging of Pancreatic Zn ²⁺ and β-Cell Function In Vivo

Noninvasive imaging of zinc ions (Zn²⁺) is crucial for understanding cellular signaling and metabolic processes, particularly in the pancreas where Zn²⁺ is coreleased with insulin. However, the development of sensitive and biocompatible magnetic resonance imaging (MRI) probes for Zn²⁺ remains challenging. Here, we report the rational design and synthesis of FeL2, a small-molecule Fe³⁺-based contrast agent engineered with imidazole-enriched chelators to achieve high Zn²⁺ affinity. Upon binding with Zn²⁺ and human serum albumin, FeL2 exhibits a marked increase in <i>r</i>₁ relaxivity, enabling in vivo visualization of glucose-stimulated Zn²⁺ secretion in the mouse pancreas. In normal mice, FeL2 produced a 25.9% enhancement in pancreatic MRI signal following glucose challenge, significantly outperforming the parent compound FeL1 (15.3%). Diabetic mice with impaired β-cell function showed minimal response, confirming the specificity of FeL2 for functional Zn²⁺ release. Biosafety evaluations revealed low toxicity and rapid renal clearance, underscoring the clinical potential of FeL2. This work establishes FeL2 as a highly sensitive and safe MRI probe for noninvasive assessment of pancreatic β-cell function, offering a promising diagnostic tool for diabetes and related metabolic disorders.