Preclinical evaluation of fluorine-18-labeled androgen receptor ligands in baboons

A noninvasive method for detecting and quantifying androgen receptors (AR) in metastatic prostate cancer may be helpful in choosing the method of treatment and in better understanding the pathophysiology of this disease. Nine previously synthesized fluorinated androgens exhibited high affinity binding to AR and showed AR-mediated uptake in the ventral and dorsal prostate of the rat. Further evaluation of these agents for PET imaging is needed since sex hormone binding globulin (SHBG), a glycoprotein which binds androgens with high affinity, is absent in rat blood but is present at high levels in the blood of primates. We chose to study three of the nine fluoro-androgens by PET in the baboon.

In this study, 16beta-[18F]fluoro-5 alpha-dihydrotestosterone (I), 16beta-[18F]fluoromibolerone (II) and 20-[18F]fluoromibolerone (III) were synthesized and studied in both a young and old male baboon using PET. Blood samples were withdrawn in three of the 10 studies and analyzed for total radioactivity and percent unmetabolized radioligand. Tissue radioactivity was evaluated semiquantitatively, using prostate absolute, standard and target to nontarget uptake values.

Prostate uptake was observed with all three 18F-androgens. At 60 min postinjection, compound I gave the highest prostate to soft tissue ratios in both baboons and prostate uptake was shown to be AR-mediated by blocking uptake through the coadministration of testosterone. Compound I gave the highest level of unmetabolized radioligand present in blood up to 45 min postinjection, and gave a 37-fold greater prostate-to-bone ratio at 2 hr postinjection in baboons compared to rats. The favorable behavior of this compound in the baboon may be related to its high affinity for SHBG.

All three compounds can be used to determine AR-positive tissue in primates. Compound I was selected for the evaluation of AR in men with prostate cancer using PET.