Ligand-Based Virtual Screening as a Path to New Chemotypes for Candidate PET Radioligands for Imaging Tauopathies

Ligand-based virtual screening (LBVS) has rarely been tested as a method for discovering new structural scaffolds for PET radioligand development. This study used LBVS to discover potential chemotype leads for developing radioligands for PET imaging of tauopathies. ZINC12, a free database of over 12 million commercially available compounds, was searched to discover novel scaffolds based on similarities to four query compounds. Thirteen high-ranking hits were purchased and assayed for their ability to compete against three tritiated radioligands at their distinct binding sites in Alzheimer's disease brain tissue. Three hits were 2-substituted 6-methoxy naphthalenes. Synthetic elaboration of this new chemotype yielded three new ligands (