11β-Substituted Estradiol Derivatives, Potential High-Affinity Carbon-11-Labeled Probes for the Estrogen Receptor: A Structure-Affinity Relationship Study

In view of their possible development as carbon-11-labeled receptor-based radiotracers for imaging estrogen-responsive breast tumors, we have synthesized a series of estradiols (1), estriols (2), 11β-ethylestradiols (3), 11β-ethylestriols (4), 11β-methoxyestradiols (5), and 11β-methoxyestriols (6), differing in the type of substituent R present at the 17α-position (a, -H; b, -CH3; c, -C≡CH; d, -C≡CCH₃; e, -Ph; f, -CH=CHMe cis), and measured their binding affinity for the estrogen receptor relative to estradiol (RBA). As expected, all the derivatives having an 11β-ethyl substituent have good binding properties (3a-d, 4a-d, RBA (25 °C): 109-3000%), and among them there are several promising candidates for carbon-11 labeling. Moxestrol (RBA (25 °C) = 185%) and its corresponding estriol derivative (4c, RBA (25 °C) = 20%) were the analogs having the highest affinity in the 11β-methoxyestradiol (5a-f) and 11β-methoxyestriol (6a-e) series, respectively; other analogs (R = Me, C=CMe, Ph, or cis-CH=CHMe) had uniformly lower RBA values.