Estrogen Receptor-Based Imaging Agents. 1. Synthesis and Receptor Binding Affinity of Some Aromatic and D-Ring Halogenated Estrogens

Steroidal and nonsteroidal estrogens substituted with halogens ortho to the phenolic hydroxyl group and 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 16a position were prepared by halogenation of estrone 3-acetate (17-enol acetate) followed by hydride reduction, and those substituted at the 16β 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 having affinities greater than the corresponding 2-substituted isomers. Introduction of a halogen (Cl, Br, I) at the 16a position of 17β-estradiol results in compounds with receptor affinities comparable to that of 17β-estradiol itself; the 16β-epimers and the estrone derivatives are bound less well. Thus, provided that they can be labeled with suitable remitting radioisotopes at sufficiently high specific activity, it appears that the A-ring fluoroestrogens and 16α-bromo- and 16α-iodoestradiol-17β are excellent candidates for receptor-based imaging of human breast tumors.