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

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

Radiolabeled 5-Iodo-3′-O-(17β-succinyl-5α-androstan-3-one)-2′-deoxyuridine and Its 5′-Monophosphate for Imaging and Therapy of Androgen Receptor-Positive Cancers: Synthesis and Biological Evaluation

“…78 Drugs bound to SHBG maintain higher circulating levels, permitting more than just the first-pass extraction into the tumor site. Moreover, recent evidence indicates that SHBG plays a local and more direct role in the cellular uptake of steroids than previously considered.…”

“…The model of SHBG interaction with its receptor in the AR-expressing cells is adopted from published data. ,− The intervention of membrane AR (mAR) in the cellular uptake is responsible for the nongenomic, rapid effects of sex steroids. − This subpopulation of AR, localized within the cell membrane, mediates the activity of ion channels and intracellular calcium levels. LNCaP cells, almost instantly after the addition of DHT, − have increased intracellular Ca 2+ levels, and rapid activation of extracellular signal-related kinases 1 and 2 is observed.…”

18 F-RB390: Innovative ligand for imaging the T877A androgen receptor mutant in prostate cancer via positron emission tomography (PET)

“…In the past, various scientists have designed besides nonsteroidal also steroidal AR radioligands either using 123 I or 18 F, but mostly choosing steroidal analogous [22][23][24]. Since the major circulating androgen testosterone has lower affinity for the AR than its metabolite DHT, most scientists placed their focus on DHT.…”

Radiochemistry

“…136 Other recently labelled compounds using nucleophilic aromatic substitution have included O-(2-fluoroethyl)-L-tyrosine, 137,138 and N-(3-fluoro-4-nitronaphthyl)-cis-5-norbornene-endo-2,3-dicarboxylic imide. 139 Derivatives of many different amine bases that participate in biochemical processes have also been labelled with fluorine-18, such thymidine, 140,141 guanine, 142 adenosine 143 and pyrimidine. 144 Most labelling is carried out to facilitate imaging in nuclear medicine.…”