Synthesis of (17 alpha,20E/Z)iodovinyl testosterone and 19-nortestosterone derivatives as potential radioligands for androgen and progesterone receptors.

To develop androgen and progesterone receptor-based radioligands for SPECT imaging we synthesized several radioiodinated 17 alpha-iodovinyl testosterone and 19-nortestosterone analogs and evaluated their biological properties. The synthesis of these compounds proceeds via the (17 alpha,20E/Z)stannyl intermediates and involves addition of tri-n-butyltin hydride to the 17 alpha-ethynyl group of the steroid using either azobisiso butyronitrile or triethylborane as a catalyst. The stannyl derivatives are stereospecifically converted to the corresponding (17 alpha,20E/Z)iodovinyl derivatives using molecular iodine, or to the [125I]iodovinyl analogs using [125I]NaI and H2O2. Androgen and progesterone receptor (AR and PgR) binding affinities were measured via a competitive in vitro binding assay. In general 19-nortestosterone derivatives showed higher receptor affinities as compared to the testosterone derivatives. In the latter series the highest PgR binding affinities were observed with the (17 alpha,20Z)iodovinyl-19-nortestosterone (IVNT) (92 vs 100 for R5020) followed by the 7 alpha-methyl analog, whereas the highest AR binding affinity was observed with the 7 alpha-Me-(17 alpha,20Z)IVNT (54 vs 100 for 5 alpha-dihydrotestosterone). These derivatives were also labeled with 125I and evaluated for their in vivo target organ uptake (prostate and estrogen-primed uterus). The highest PgR-mediated target tissue uptake was observed with the (17 alpha,20Z)-[125I]IVNT and its 7 alpha-methyl derivatives whereas only one derivative, the 7 alpha-Me-(17 alpha,20Z)-[125I]IVNT, showed AR-mediated dorsal prostate retention. Although some of the IVNT derivatives have interesting binding properties, the lack of in vivo selectivity does suggest that the 123I-labeled analogs are unlikely to be suitable for imaging of AR and PgR-rich tissues.