A potential radioiodinated ligand for androgen receptor: 7α-methyl-17α-(2'-(E)-iodovinyl)-19-nortestosterone

Article abstract of DOI:10.1021/jm00107a021

The presence of androgen receptor (AR) in prostate cancer has been linked to the androgen-dependent nature of the tumor and has also been shown to have prognostic significance; it also appears to be a positive prognostic indicator in breast cancer. However, due to the relatively low AR concentrations in most tumors and the inherently low specific activity of tritium, the assay of AR based on available ³H-ligands is not sensitive enough to measure accurately the amount of receptor in small specimens. A ¹²⁵I-ligand like those available for the estrogen and progesterone receptors would be helpful, but development of such a ligand for AR has not been very successful. Although several androgen analogues containing iodine, bromine, or selenium have been synthesized specifically as potential probes for AR, none have shown any significant affinity or specificity for the receptor. We therefore undertook the synthesis of new potential AR ligands which could be radioiodinated, and determined their affinities for AR (from rat uterus and MCF-7 human breast cancer cells) by using a competition assay. We have examined both 5α-dihydrotestosterone (5α-DHT) and 19-nortestosterone analogues and have identified two such compounds which showed high AR affinity: (17α,20E)-17β-hydroxy-21-iodo-5α-pregn-20-en-3-one (17α-((E)-iodovinyl)-5α-DHT, 9) and 17β-hydroxy-7α-methyl-(17α,20E)-21-iodo-19-norpregna-4,20-dien-3- one (7α-methyl-17α-((E)-iodovinyl)-19-nortestosterone, 11). In fact, the affinity of the latter for human AR was found to be superior to that of 5α-DHT itself. These iodovinyl analogues could be easily prepared in the radioiodinated form, and should prove to be extremely useful in assaying low levels of AR in small specimens.