Synthesis and evaluation of estrogen receptor β-selective ligands: Fluoroalkylated indazole estrogens

It is important to identify selective ligands for the estrogen receptor subtypes ERα or ERβ to evaluate them as pharmaceutical targets in breast cancer. To develop ERβ-selective ligands as PET imaging agents, a series of aryl indazole estrogen analogues substituted at the C3 position with fluoroethyl and fluoropropyl groups were synthesized and evaluated for their relative binding affinities and selectivities for ERα vs ERβ. The fluoroethylated indazole estrogen (FEIE, 1i) and fluoropropylated indazole estrogen (FPIE, 1h) showed 41-fold and 17-fold ERβ/ERα selectivity, respectively. However, their binding affinities to ERα and ERβ were very low.