11 beta-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), 11 beta-ethylestradiols (3), 11 beta-ethylestriols (4), 11 beta-methoxyestradiols (5), and 11 beta-methoxyestriols (6), differing in the type of substituent R present at the 17 alpha-position (a, -H; b, -CH3; c, -C identical to CH; d, -C identical to 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 11 beta-ethyl substituent have good binding properties (3a-d, 4a-d, RBA (25 degrees C): 109-3000%), and among them there are several promising candidates for carbon-11 labeling. Moxestrol (RBA (25 degrees C) = 185%) and its corresponding estriol derivative (4c, RBA (25 degrees C) = 20%) were the analogs having the highest affinity in the 11 beta-methoxyestradiol (5a-f) and 11 beta-methoxyestriol (6a-e) series, respectively; other analogs (R = Me, C identical to CMe, Ph, or cis-CH = CHMe) had uniformly lower RBA values.
Napolitano
E
E
Scuola Normale Superiore, Piazza dei Cavalieri, Pisa, Italy.
Fiaschi
R
R
Carlson
K E
KE
Katzenellenbogen
J A
JA
D001665:Binding Sites; D002247:Carbon Isotopes; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015335:Molecular Probes; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D002247:Carbon Isotopes; D015335:Molecular Probes; D011960:Receptors, Estrogen; D004958:Estradiol