<i>O</i> -Position Electronegativity Dependent Activity for Specific-Rapid Response to Superoxide Anion and Its Imaging for Epilepsy Mediated by Ferroptosis Pathway

Epilepsy is a chronic neurological disorder characterized by abnormal, excessive, and synchronous firing of neurons in the brain. Numerous biological studies have shown that the seizure and progression of epilepsy can directly activate the ferroptosis pathway, leading to dysregulation of physiological signaling and the induction of oxidative stress. As a key member of the reactive oxygen species (ROS) family, O₂^•- plays an important regulatory and signaling role in the nervous system. Investigating the dynamic regulation of O₂^•- between epilepsy and the ferroptosis pathway is crucial. Thus, high-resolution specific imaging of O₂^•- in the brain is urgently needed. Regarding the issue of being susceptible to interference from other reactive oxygen species, we innovatively introduced a series of push-pull electron groups (-F, -Cl, -Br, -I, -OCH₃, -CF₃, -H) to adjust the activity of the trifluorosulfonic acid group. <b>LYC-CF</b>_<b>3</b> was founded to be specific for O₂^•-. Meanwhile, due to the isophorone fluorophore, the probe exhibits enhanced lipophilicity, red-shifted emission wavelengths, and the ability to cross the blood-brain barrier. Using <b>LYC-CF</b>_<b>3</b>, we constructed a brain imaging epilepsy model under ferroptosis inducers and inhibitors as a marker for O₂^•-. For the first time, we revealed ferroptosis pathways mediating epilepsy. These findings provide a new theoretical basis and potential intervention strategy for the early diagnosis and treatment of epilepsy.