Development of radioiodinated nonsteroidal androgen receptor ligands for spect imaging of prostate cancer

The appropriate treatment strategy for prostate cancer is critically dependent on its accurate staging (1). Current screening techniques (CT, MRI, Ultrasound) fail to reliably distinguish clinically-localized disease from metastatic disease. A reliable noninvasive method for detection of prostate cancer metastases would thus be of immense clinical benefit for a) disease staging b) implementing the appropriate treatment strategy c) monitoring the effects of therapy. To address this need, many research groups have focused on the development of radiolabeled androgen receptor (AR) ligands for prostate cancer imaging, based on the observation that most prostate tumors and metastases express AR (2,3). The majority of these studies to date have focused on steroid-based ligands (2,4,5). The antiandrogens RU 59063 and RU 58841 (Table l), are prototypes of a new series of nonsteroidal androgen receptor ligands that display high AR affinity and selectivity (6,7). The ease of synthesis and structural modification of these compounds as compared to steroid-based AR ligands, prompted us to select them as leads for development of a SPECT AR radioligand. We have previously shown that substitution of the trifluoromethyl group of RU 59063 with iodine leads to an improvement in AR binding affinity (8). Accordingly, a series of iodinated analogs of RU 59063 and RU 58841 was synthesized for investigation as in vivo AR radioligands (Table 1). Compounds 1-4 were synthesized from 4-cyano-3-iodoaniline using previously reported methods (8). Radioiodination of compounds 1-4 with iodine-125 were achieved in 50-65% radiochemical yield by an ammonium sulfate catalyzed solid phase exchange procedure (Scheme 1). Radiolabeled products were purified either by elution through an anion exchange resin or