Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 49, Issue 8, Pages 2496-2511Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm0512037
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Funding
- NCI NIH HHS [5R37 CA 25836, R37 CA025836-26, R37 CA025836] Funding Source: Medline
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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 ER alpha and ER beta 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 ERa 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.
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