7α-¹⁸F-fluoromethyl-dihydrotestosterone and 7α- ¹⁸F-fluoromethyl-nortestosterone: Ligands to determine the role of sex hormone-binding globulin for steroidal radiopharmaceuticals

Sex hormone-binding globulin (SHBG) is believed to play a key role in steroidal radiopharmaceutical delivery to target tissues in humans. To better understand the action of SHBG, we have synthesized and tested in vivo 2 novel ¹⁸F-labeled androgens: 7α-¹⁸F-fluoromethyl- dihydrotestosterone (7α-¹⁸F-FM-DHT) and 7α- ¹⁸F-fluoromethyl-nortestosterone (7α-¹⁸F-FM-norT). Both 7α-¹⁸F-FM-DHT and 7α-¹⁸F-FM-norT have high affinity for the androgen receptor (AR); however, 7α- ¹⁸F-FM-DHT has a high affinity for SHBG, whereas 7α- ¹⁸F-FM-norT has a relatively low affinity. Methods: We developed an efficient radiochemical synthesis for both 7α-¹⁸F-FM-DHT and 7α-¹⁸F-FM-norT, producing them in good radiochemical yield and high specific activity. Biodistribution studies of both compounds were done on diethylstilbestrol-pretreated and DHT-blocked Sprague-Dawley male rats. Metabolism studies were done to determine the amount of intact ligand in the prostate. Results: We obtained 7α-¹⁸F-FM-DHT and 7α- ¹⁸F-FM-norT in radiochemical yields of about 30% and radiochemical purities of greater than 99%. Rat biodistribution studies showed selective AR-mediated uptake in the prostate for both compounds. Both compounds showed relatively little defluorination, but the norT analog was more metabolically stable than the DHT analog. Conclusion: These studies show that 7α- ¹⁸F-FM-DHT and 7α-¹⁸F-FM-norT have potential for use in human clinical imaging trials to evaluate more definitively the role of SHBG in radiotracer delivery of steroidal systems to target tissues.