Synthesis of 7α-(Fluoromethyl)dihydrotestosterone and 7α-(Fluoromethyl)nortestosterone, Structurally Paired Androgens Designed To Probe the Role of Sex Hormone Binding Globulin in Imaging Androgen Receptors in Prostate Tumors by Positron Emission Tomography

Abstract

Although prostate cancer growth is regulated by androgens through the androgen receptor (AR), in vitro assays of AR levels in prostate tumors have limited prognostic value. This might be improved by direct measurement of tumor AR in vivo using positron emission tomography (PET) imaging with fluorine-18-labeled androgens. Most AR PET imaging agents have been designed to limit steroid binding to serum proteins, but there is evidence that binding to sex hormone binding globulin (SHBG) might enhance tumor uptake. To probe the role of SHBG in prostate tumor uptake of PET imaging agents, we have synthesized two fluoro steroids, 7alpha-(fluoromethyl)dihydrotestosterone (7alpha-FM-DHT) and 7alpha-(fluoromethyl)nortestosterone (7alpha-FM-norT), by a route amenable to their labeling with [18F]fluoride ion. Both compounds have high affinity for AR, but 7alpha-FM-norT has much lower affinity for SHBG. Thus, these two fluoro steroids are well matched in terms of their site of fluorine labeling, similarity of structure, and equivalent AR binding affinity-but contrasting SHBG binding-and therefore can be used as agents for evaluating the role of SHBG binding in the target tissue uptake of AR PET imaging agents in humans.