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 (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.

基于配体的虚拟筛选（LBVS）在探索用于正电子发射断层扫描（PET）放射性配体开发的新型结构骨架方面鲜有应用。本研究利用LBVS技术，旨在发现开发tauopathies PET影像学放射性配体的潜在化学类型先导化合物。通过ZINC12，一个包含超过1200万个商业化化合物的免费数据库，基于与四种查询化合物的相似性，搜寻新型骨架。购入并检测了十三种高排名的候选化合物，评估其在阿尔茨海默病脑组织中对三种三氟标记的放射性配体在不同结合位点上的竞争能力。其中三种为2-取代的6-甲氧基萘。对该新型化学类型进行合成扩展，得到三种新的配体（25号、26号和28号），它们对[3H]6（flortaucipur）神经纤维缠结结合位点表现出高亲和力。化合物28显示出异常高的亲和力（Ki，7 nM）以及其他作为PET放射性配体候选者的理想特性，包括低拓扑极性表面积、适中的计算对数分配系数，以及易于用碳-11进行标记。LBVS似乎在发现潜在PET放射性配体的新型化学类型方面具有独特的价值。