Highly Selective Dual-Modal Probe for Photoacoustic and Magnetic Resonance Imaging of the Labile Cu2+ Pool in the Liver

Copper ions (Cu²⁺) play vital roles in human physiology, and their dyshomeostasis is associated with diseases such as hepatocellular carcinoma, Alzheimer’s disease, and Wilson’s disease. Cu²⁺ imaging technologies facilitate the investigation of Cu²⁺ dynamics in biological systems. However, developing highly selective and sensitive Cu²⁺ probes that can overcome interference from physiologically abundant Zn²⁺ remains a key challenge. In this study, we design and synthesize a Cu²⁺-activated dual-modal probe (BHGd) for photoacoustic (PA) and magnetic resonance (MR) imaging, which exhibits remarkable specificity for Cu²⁺. Impressively, BHGd demonstrates exceptional selectivity for Cu²⁺ even in the presence of a 1000-fold excess of Zn²⁺. BHGd binds Cu²⁺ in a 1:1 stoichiometry, forming a stable ternary complex in the presence of human serum albumin (HSA), which enhances PA signals by 5.9-fold and increases longitudinal relaxivity (r₁) by 114.9%. Furthermore, in vivo experiments demonstrate that BHGd enables precise monitoring of labile Cu²⁺ fluctuations in the liver of mice, achieving a remarkable 59% increase in PA signal intensity and a 30% enhancement in MR signal contrast. The systematic investigation demonstrates that BHGd can serve as a powerful molecular probe for investigating copper metabolism in living systems. Our breakthrough addresses the long-standing challenge of Cu²⁺/Zn²⁺ discrimination and provides a design principle for next-generation metal ion probes, with significant potential for diagnosing Cu²⁺ imbalance-related disorders, monitoring therapeutic responses, and advancing biomedical research.