Dual-State Emission Fe²⁺-Activation Probe Capable of High-Contrast Brain Imaging Reveals an Age-Dependent Accumulation of Fe²⁺ in the Brain

Brain aging is accompanied by alterations in iron homeostasis. However, existing methods remain challenging for specific and real-time imaging of brain iron in vivo. Herein, we developed a fluorescent probe, NRP-Boc-Fe, for visualizing dynamic changes of ferrous ions (Fe²⁺) in the brain. The probe employs an N-oxide as the specific recognition site for Fe²⁺, achieving sensitive and selective responses to Fe²⁺. In addition, the fluorophore of the probe has dual-state emission (DSE) characteristics, with strong emissions in both dilute solutions and solid state, ensuring that fluorescence signals are unaffected by molecular aggregation or monomer state in complex biological environments. More importantly, NRP-Boc-Fe exhibits excellent blood-brain barrier (BBB) permeability, allowing noninvasive, real-time, and rapid imaging of brain Fe²⁺. Using this probe, we successfully revealed a significant age-dependent increase in Fe²⁺ levels within aging brains, establishing a direct correlation between Fe²⁺ accumulation and the aging process. This discovery not only validates Fe²⁺ as a potential biomarker for brain aging but also offers new insights into brain aging and a prospective novel imaging tool for exploring Fe²⁺-related brain diseases.