Fluorinated androgens and progestins: molecular probes for androgen and progesterone receptors with potential use in positron emission tomography.
In order to develop imaging agents for receptor-positive tumors of the breast and prostate, we have investigated the binding affinity of several fluorine-substituted steroids in the testosterone and nortestosterone series for the androgen receptor and the progesterone receptor. The 6 alpha- and 11 beta-fluoro-, and 16 alpha-fluoroalkyl-substituted steroids were prepared by an olefin bromofluorination reaction followed by dehydrobromination or reductive debromination. The 17 alpha-fluoromethyl derivatives were prepared by fluoride ion attack on the 17-spiroepoxide or 17-spiro sulfate and the 17 alpha-fluoropropynyl derivative, by reaction of a propargyl alcohol precursor with diethylaminosulfur trifluoride. Of the compounds synthesized, 17 alpha-(3-fluoro-I-propynyl)nortestosterone was found to possess the highest binding affinity and selectivity for the progesterone receptor, and 11 beta-fluoronordihydrotestosterone had the greatest affinity for the androgen receptor. Both receptor systems seem to tolerate reasonably well the substitution of fluorine for hydrogen.
D000728:Androgens / Q000138:chemical synthesis / Q000378:metabolism; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D005461:Fluorine; D008024:Ligands; D011372:Progestins / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D011944:Receptors, Androgen / Q000032:analysis* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000032:analysis* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed; D014599:Uterus / Q000032:analysis
D000728:Androgens; D008024:Ligands; D011372:Progestins; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D005461:Fluorine