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

Byung Seok Moon, Kathryn E Carlson, John A Katzenellenbogen, Tae Hyun Choi, Dae Yoon Chi, Jung Young Kim, Gi Jeong Cheon, Hun Yeong Koh, Kyo Chul Lee, Gwangil An

Index: Bioorg. Med. Chem. 17 , 3479-88, (2009)

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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.