Synthesis of C-6 fluoroandrogens: evaluation of ligands for tumor receptor imaging.
Seven androgens, substituted with fluorine at C-6, were prepared as potential imaging agents for androgen receptor-positive prostate tumors and were evaluated in vitro in terms of their lipophilicity and their relative binding affinities (RBA, relative to R 1881 = 100) for the androgen receptor and for sex steroid binding protein. Introduction of a fluorine atom into the C-6 position of an androgen generally decreases binding affinity to the androgen receptor, except in the two cases: 6 alpha-fluoro-19-nor-testosterone (RBA = 41.6 versus 30.6 for the unsubstituted steroid) and 6 alpha-fluorotestosterone (RBA = 8.9 versus 6.6). Receptor binding of the C-6 fluoro-androgens is also stereospecific, showing higher binding affinities for the alpha-epimers compared to the corresponding beta-epimers (4:1-15:1). Binding affinity to sex steroid binding protein is the lowest with 19-nor-testosterone, which is also the least lipophilic androgen studied. Based on the binding properties of compounds in this series, 6 alpha-fluoro-19-nor-testosterone appears to have the most promise as a tumor imaging agent.
Choe
Y S
YS
Department of Chemistry, University of Illinois, Urbana 61801, USA.
Katzenellenbogen
J A
JA
D000728:Androgens / Q000138:chemical synthesis*; D000731:Androstanes / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015741:Metribolone / Q000378:metabolism; D008956:Models, Chemical; D009376:Neoplasms, Hormone-Dependent / Q000000981:diagnostic imaging; D009635:Norandrostanes / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging; D011944:Receptors, Androgen / Q000378:metabolism*; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism*; D013259:Steroids, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014055:Tomography, Emission-Computed
D000728:Androgens; D000731:Androstanes; D008024:Ligands; D009635:Norandrostanes; D011944:Receptors, Androgen; D012738:Sex Hormone-Binding Globulin; D013259:Steroids, Fluorinated; D015741:Metribolone