7-¹⁸F-Fluoromethyl-Dihydrotestosterone and 7-¹⁸F-Fluoromethyl-Nortestosterone: Ligands to Determine the Role of Sex Hormone–Binding Globulin for Steroidal Radiopharmaceuticals

¹ Department of Chemistry, University of Illinois, Urbana, Illinois
² Washington University School of Medicine, St. Louis, Missouri

^* To whom correspondence should be addressed. E-mail: jkatzene{at}uiuc.edu.

	Abstract

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: 7-¹⁸F-fluoromethyl-dihydrotestosterone (7-¹⁸F-FM-DHT) and 7-¹⁸F-fluoromethyl-nortestosterone (7-¹⁸F-FM-norT). Both 7-¹⁸F-FM-DHT and 7-¹⁸F-FM-norT have high affinity for the androgen receptor (AR); however, 7-¹⁸F-FM-DHT has a high affinity for SHBG, whereas 7-¹⁸F-FM-norT has a relatively low affinity. Methods: We developed an efficient radiochemical synthesis for both 7-¹⁸F-FM-DHT and 7-¹⁸F-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 7-¹⁸F-FM-DHT and 7-¹⁸F-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 7-¹⁸F-FM-DHT and 7-¹⁸F-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.

Key Words: PET, ¹⁸F, prostate cancer, androgen receptor, sex hormone–binding globulin