posted on 2024-08-07, 07:04authored byBryan
T. Hurtle, Susovan Jana, Lisheng Cai, Victor W. Pike
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 (25, 26, and 28) with high affinity
for the [3H]6 (flortaucipur) neurofibrillary
tangle binding site. Compound 28 showed remarkably high
affinity (Ki, 7 nM) and other desirable
properties for a candidate PET radioligand, including low topological
polar surface area, moderate computed log D, and amenability for labeling with carbon-11. LBVS appears to be
uniquely valuable for discovering new chemotypes for candidate PET
radioligands.