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 meth od of treatment and in better understanding the pathophysiology of thi s disease. Nine previously synthesized fluorinated androgens exhibited high affinity binding to AR acid showed AR-mediated uptake in the ven tral and dorsal prostate of the rat. Further evaluation of these agent s 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 . Methods: In this study, 16 beta-[F-18]fluoro-5 alpha-dihydrotestoste rone (I), 16 beta-[F-18]fluoromibolerone (II) and 20-[F-18]fluoromibol erone (III) were synthesized and studied in both a young and old male baboon using PET. Blood samples were withdrawn in three of the 10 stud ies and analyzed for total radioactivity and percent unmetabolized rad ioligand. Tissue radioactivity was evaluated semiquantitatively, using prostate absolute, standard and target to nontarget uptake values. Re sults: Prostate uptake was observed with all three F-18-androgens. At 60 min postinjection, compound I gave the highest prostate to soft tis sue ratios in both baboons and prostate uptake was shown to be AR-medi ated 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 prost ate-to-bone ratio at 2 hr postinjection in baboons compared to rats. T he favorable behavior of this compound in the baboon may be related to its high affinity for SHBG. Conclusion: All three compounds can be us ed to determine AR-positive tissue in primates, Compound I was selecte d for the evaluation of AR in men with prostate cancer using PET.