Fluorine-substituted cyclofenil derivatives as estrogen receptor ligands: Synthesis and structure-affinity relationship study of potential positron emission tomography agents for imaging estrogen receptors in breast cancer

Jai Seo, John S. Comninos, Dae Yoon Chi, Dong Wook Kim, Kathryn E. Carlson, John A. Katzenellenbogen

Research output: Contribution to journalArticle

41 Scopus citations


In a search for estrogen receptor (ER) ligands to be radiolabeled with fluorine-18 for imaging of ER-positive breast tumors with positron emission tomography (PET), we investigated cyclofenil analogues substituted at the C3 or C4 position of the cyclohexyl group. McMurry coupling of 4,4′- dihydroxybenzophenone with various ketones produced key cyclofenil intermediates, from which C3 and C4 substituents containing alkyl and various oxygen or fluorine-substituted alkyl groups were elaborated. Binding assays to both ERα and ERβ revealed that the C3 site is more tolerant of steric bulk and polar groups than the C4 site, consistent with a computational model of the ERα ligand binding pocket. Fluorine substitution is tolerated very well at some sites, giving some compounds having affinities comparable to or higher than that of estradiol. These fluoro and fluoroalkyl cyclofenils merit further consideration as fluorine-18 labeled ER ligands for PET imaging of ERs in breast tumors.

Original languageEnglish (US)
Pages (from-to)2496-2511
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number8
StatePublished - Apr 20 2006
Externally publishedYes


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this