This research presents an innovative image-guided synthesis approach to identify potent histone deacetylase inhibitors (HDACi) with enhanced permeability across the blood-brain barrier (BBB). By leveraging imaging techniques, we systematically screened a library of compounds to pinpoint those capable of effectively penetrating the BBB. Our findings reveal several novel HDAC inhibitors that demonstrate significant therapeutic potential for central nervous system disorders. This study not only advances the understanding of HDAC inhibition but also highlights the importance of targeted synthesis methodologies in developing drug candidates that can successfully navigate the challenges of brain delivery.