Estrogen receptor based imaging agents. 2. Synthesis and receptor binding affinity of side-chain halogenated hexestrol derivatives

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Abstract
As potential imaging agents for human breast tumors to assist in therapeutic selection, a series of hexestrol analogs were synthesized bearing the halogens fluorine, chlorine, bromine and iodine at the terminus of the hexane chain. The binding affinity of these compounds for the estrogen receptor from uterine tissues forms a monotonically decreasing series, starting at 129% of that of estradiol for the fluoro analog and decreasing to 60% for the iodo analog. Such a modest decrease in binding affinity may reflect the preference of the receptor for lipophilic groups and for substituents of moderate steric size at this site, parameters which change in opposite directions in the halogen sequence going from fluorine to iodine. Three estrogenic bis(trifluoromethyl)diphenylethylenes also showed substantial binding affinities for the estrogen receptor. In terms of ease of radiolabeling and high receptor binding selectivity, the most promising candidate for a breast tumor imaging agent in these series is the chain terminal fluorohexestrol.