Steroidal and
nonsteroidal estrogens substituted with
halogens ortho to the phenolic
hydroxyl group in the D ring at C-16 have been prepared as potential
estrogen receptor-based imaging agents for human
breast tumors.
Estrogens bearing an aromatic
fluorine ortho to a phenolic
hydroxyl group were prepared by the Schiemann reaction on the corresponding methyl
esters; other ortho-halogenated
estrogens were prepared by direct halogenation. Steroidal
estrogens substituted at the 16 alpha position were prepared by halogenation of
estrone 3-acetate (17-enol acetate) followed by hydride reduction, and those substituted at the 16 beta position were prepared by epimerization prior to reduction. The binding affinity of these halogenated
estrogens to the uterine
estrogen receptor was measured relative to that of [3H]
estradiol by a competitive binding assay. All of the monosubstituted ortho-fluorinated
estrogens show very high binding affinity for the receptor (64--250% that of
estradiol). The monosubstituted and symmetrically disubstituted bromo- and iodohexestrols and 2- and 4-substituted estradiols have binding affinities considerably lower than those of the fluoro compounds, the 4-substituted estradiols have affinities greater than the corresponding 2-substituted isomers. Introduction of a
halogen (Cl, Br, I) at the 16 alpha position of
17 beta-estradiol results in compounds with receptor affinities comparable to that of
17 beta-estradiol itself; the 16 beta-epimers and the
estrone derivatives are bound less well. Thus, provided that they can be labeled with suitable gamma-emitting
radioisotopes at sufficiently high specific activity, it appears that the A-ring fluoroestrogens and 16 alpha-bromo- and 16 alpha-iodoestradiol-17 beta are excellent candidates for receptor-based imaging of human
breast tumors.