Synthesis of a carbon-11 labeled nonsteroidal antiandrogen as a potential radioligand for pet imaging of prostate cancer

The hormone dependency of prostate cancer is well established and androgen receptor (AR) expression is frequently observed in primary prostate tumors and metastases (1). As a consequence, the development of radioligands that target the AR for prostate tumor imaging is an active area of research (2). The majority of these studies to date have focused on steroid-based ligands, including the naturally occurring androgens (testosterone, dihydrotestosterone) and synthetic steroids (mibolerone, metribolone) (3,4). The recent emergence of AR-selective, high-affinity, nonsteroidal antiandrogens such as RU 59063, (Table l), offers a usehl alternative approach towards AR radioligand development (5). Our goal in this study was to develop a suitable carbon-1 1 labeled nonsteroidal AR radioligand for PET imaging of prostate cancer. We recently showed that replacement of the trifluoromethyl group of RU 59063 with iodine (DTIB, Table 1) leads to a 3-fold enhancement in AR binding affinity (6). This observation led us to synthesize the N-methylated hydantoin and thiohydantoin derivatives (laJb), which were subsequently shown to retain high affinity towards AR (Table 1). Since the synthesis of ["C]lJ by direct N-["C]methylation of its normethyl precursor is not feasible (due to preferential methylation on sulfur), the N-methyl derivative was selected for carbon-1 1 labeling. We report here the radiosynthesis of [ " C ] b for evaluation as a AR radioligand for PET.