Chemical synthesis of fluorinated and iodinated 17?-HSD3 inhibitors and evaluation for imaging prostate cancer tumors and tissue biodistribution

Prostate cancer is the most common cancer among men and the development of new therapeutic agents is needed for its treatment and/or diagnosis. 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD3) is involved in the production of androgens, which stimulates the proliferation of prostate cancer cells. Piperazinomethylandrosterone sulfonamide derivatives were developed as 17 beta-HSD3 inhibitors and the concentration of a representative sulfonamide derivative (compound 1) was found to accumulate in prostate tumor tissues relatively to plasma in a mouse xenograft experiment. This finding gives us the opportunity to specifically target the prostate cancer tumors through the development of a radiolabelled version of compound 1 toward targeted molecular radiotherapy or radioimaging diagnosis. The chemical synthesis of fluorinated and iodinated analogs of compound 1 was achieved, leading to a series of compounds with similar levels of inhibition as the initial candidate. From 17 beta-HSD3 inhibition activity, molecular modeling and mouse plasma-concentration studies, the most promising compound of this series was selected, its 18F-radiolabelled version (18F-3) synthesized, and imaging/biodistribution studies engaged. When injected in mice, however, 18F-3 uptake in the target tissues (LNCaP[17 beta-HSD3] tumors and testicles) was not sufficient to allow their visualization by positron emission tomography. Plasma concentration values of compounds 3-8 administered orally, however, showed that the para-iodo compound 7 is the most metabolically stable and could therefore be an interesting alternative for radiolabelling and radiotreatment.

Automated summary

A compound that inhibits 17 beta-HSD3 activity and accumulates in prostate tumor tissues has been discovered. This finding opens up the possibility of targeted molecular radiotherapy or radioimaging diagnosis using radiolabelled versions of the compound.