Synthesis and evaluation of aryl-substituted diarylpropionitriles, selective ligands for estrogen receptor beta, as positron-emission tomographic imaging agents

Bioorg Med Chem. 2009 May 1;17(9):3479-88. doi: 10.1016/j.bmc.2009.02.064. Epub 2009 Mar 9.

Abstract

We have investigated halogen-substituted non-steroidal estrogens with selective binding affinity for the estrogen receptor beta (ERbeta that might be used for imaging the levels of this ER-subtype in breast tumors by positron emission tomography (PET). Based on diarylpropionitrile (DPN, 1a), a compound previously reported that has a 72-fold binding selectivity for ERbeta, we developed a series of DPN analogs having methyl-, hydroxyl-, and halogen substituents, including fluoroethyl and fluoropropyl groups. In competitive radiometric binding assays with [(3)H]estradiol, all of these DPN analogs showed high ERbeta/ERalpha selectivity; while the selectivity varied, in some cases it reached nearly 300-fold (RBA: ERalpha, 0.023%; ERbeta, 6.25%). The absolute ERbeta binding affinities, however, were not sufficient to merit further consideration for developing these ligands as PET imaging agents.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Estrogen Receptor beta / chemistry
  • Estrogen Receptor beta / metabolism*
  • Fluorine Radioisotopes / chemistry
  • Humans
  • Kinetics
  • Ligands
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Positron-Emission Tomography
  • Propionates / chemical synthesis*
  • Propionates / chemistry
  • Protein Binding
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • 2,3-bis(4-hydroxyphenyl)-propionitrile
  • Estrogen Receptor beta
  • Fluorine Radioisotopes
  • Ligands
  • Nitriles
  • Propionates
  • Radiopharmaceuticals