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

• Published in: Journal of medicinal chemistry 1980-09, Vol.23 (9), p.1002-1008
• Main Authors: Goswami, Ramanuj, Harsy, Stephen G, Heiman, Daniel F, Katzenellenbogen, John A
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - diagnostic imaging; Female; Hexestrol - analogs & derivatives; Hexestrol - chemical synthesis; In Vitro Techniques; Radionuclide Imaging; Receptors, Estrogen - metabolism; Sheep; Structure-Activity Relationship; Uterus - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00183a008

We have synthesized as potential imaging agents for human breast tumors a series of hexestrol analogues 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 analogue and decreasing to 60% for the iodo analogue. Such a modest decrease in binding affinity is thought to 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, prepared by DuPont, also showed substantial binding affinities for the estrogen receptor. In terms of ease of radiolabeling and high receptor binding selectivity, the compound that appears to be the most promising candidate for a breast tumor imaging agent in these series is the chain terminal fluorohexestrol.