Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Annals of Nuclear Medicine
Published in: Annals of Nuclear Medicine 1/2017

01-01-2017 | Original Article

Synthesis and basic evaluation of 7α-(3-[18F]fluoropropyl)-testosterone and 7α-(3-[18F]fluoropropyl)-dihydrotestosterone

Authors: Mayumi Okamoto, Kyosuke Naka, Kiichi Ishiwata, Isao Shimizu, Jun Toyohara

Published in: Annals of Nuclear Medicine | Issue 1/2017

Login to get access

Abstract

Objective

7α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized fluoropropyl derivatives of 7α-(3-[18F]fluoropropyl)-testosterone ([18F]7) and 7α-(3-[18F]fluoropropyl)-dihydrotestosterone ([18F]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats.

Methods

We synthesized [18F]7 and [18F]15. In vitro binding to recombinant rat AR ligand binding domain protein was determined using a competitive radiometric ligand-binding assay with the high-affinity synthetic androgen [17α-methyl-3H]-methyltrienolone ([3H]R1881). In vivo biodistribution was performed in mature male rats treated with diethylstilbestrol (chemical castration). A blocking study was performed by co-administration of dihydrotestosterone (36 µg/animal).

Results

7α-(3-Fluoropropyl)-testosterone (7) and 7α-(3-fluoropropyl)-dihydrotestosterone (15) showed competitive binding to recombinant rat AR ligand binding domain protein. The IC50 value of 15 (13.0 ± 3.3 nM) was higher than 7 (47.8 ± 10.0 nM). In contrast to the AR binding affinity, the ventral prostate uptake of [18F]7 and [18F]15 at 2 h post-injection was similar (0.07 % injected dose/g of tissue). A blocking study indicated that specific binding of [18F]15 is observed in the ventral prostate. [18F]7 and [18F]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents.

Conclusion

[18F]15 is better than [18F]7 in terms of radiochemical yield, in vitro binding affinity, prostate specific binding and stability against in vivo metabolic de-fluorination. However, the net uptake level of [18F]15 in prostate might be insufficient for in vivo visualization. Although [18F]7 and [18F]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16β-[18F]fluoro-5α-dihydrotestosterone. It is also revealed that the shorter side chain length of 7α-[18F]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [18F]15, in terms of net prostate uptake and in vivo metabolic stability.
Appendix
Available only for authorised users
Literature
1.
2.
Shiota M, Eto M. Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer. Int J Urol. 2016;23:360–9.CrossRefPubMed
3.
Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4:365–80.PubMedPubMedCentral
4.
Crawford ED, Higano CS, Shore ND, Hussain M, Petrylak DP. Treating patients with metastatic castration resistant prostate cancer: a comprehensive review of available therapies. J Urol. 2015;194:1537–47.CrossRefPubMed
5.
6.
Talbot JN, Gilgorov J, Nataf V, Montravers F, Huchet V, Michaud L, et al. Current applications of PET imaging of sex hormone receptors with a fluorinated analogue of estradiol or testosterone. Q J Nucl Med Mol Imaging. 2015;59:4–17.PubMed
7.
8.
Hospers GA, Helmond FA, de Vries EG, Dierckx RA, de Vries EF. PET imaging of steroid receptor expression in breast and prostate cancer. Curr Pharm Des. 2008;14:3020–32.CrossRefPubMed
9.
Liu A, Katzenellenbogen JA, VanBrocklin HF, Mathias CJ, Welch MJ. 20-[18F]Fluoromibolerone, a positron-emitting radiotracer for androgen receptors: synthesis and tissue distribution studies. J Nucl Med. 1991;32:81–8.PubMed
10.
Liu A, Dence CS, Welch MJ, Katzenellenbogen JA. Fluorine-18-lableled androgens: radiochemical synthesis and tissue distribution studies on six fluorine-substituted androgens, potential imaging agents for prostatic cancer. J Nucl Med. 1992;33:724–34.PubMed
11.
Choe YS, Lidström PJ, Chi DY, Bonasera TA, Welch MJ, Katzenellenbogen JA. Synthesis of 11β-[18F]fluoro-5α-dihydrotestosterone and 11β-[18F]fluoro-19-nor-5α-dihydrotestosterone: preparation via halofluoronation-reduction, receptor binding, and tissue distribution. J Med Chem. 1995;38:816–25.CrossRefPubMed
12.
Garg PK, Labaree DC, Hoyte RM, Hochberg RB. [7α-18F]Fluoro-17α-methyl-5α-dihydrotestosterone: a ligand for androgen receptor-mediated imaging of prostate cancer. Nucl Med Biol. 2001;28:85–90.CrossRefPubMed
13.
Parent EE, Dence CS, Sharp TL, Welch MJ, Katzenellenbogen JA. 7α-18F-Fluoromethyl-dihydrotestosterone and 7α-18F-fluoromethyl-nortestosterone: ligands to determine the role of sex hormone-binding globulin for steroidal radiopharmaceuticals. J Nucl Med. 2008;49:987–94.CrossRefPubMed
14.
Larson SM, Morris M, Gunther I, Beattie B, Humm JL, Akhurst TA, et al. Tumor localization of 16β-18F-fluoro-5α-dihydrotestosterone vs. 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med. 2004;45:366–73.PubMed
15.
Zanzonico PB, Finn R, Pentlow KS, Erdi Y, Beattie B, Akhurst T, et al. PET-based radiation dosimetry in man of 18F-fluorodihydroteststerone, a new radiotracer for imaging prostate cancer. J Nucl Med. 2004;45:1966–71.PubMed
16.
Dehdashti F, Picus J, Michalski JM, Dence CS, Siegel BA, Katzenellenbogen JA, et al. Positron tomographic assessment of androgen receptors in prostatic carcinoma. Eur J Nucl Med Mol Imaging. 2005;32:344–50.CrossRefPubMed
17.
Beattie BJ, Smith-Jones PM, Jhanwar YS, Schöder H, Schmidtlein R, Morris MJ, et al. Pharmacokinetic assessment of the uptake of 16β-18F-fluoro-5α-dihydrotestosterone (FDHT) in prostate tumors as measured by PET. J Nucl Med. 2010;51:183–92.CrossRefPubMedPubMedCentral
18.
Labaree DC, Hoyte RM, Nazareth LV, Weigel NL, Hochberg RB. 7α-Iodo and 7α-fluoro steroids as androgen receptor-mediated imaging agents. J Med Chem. 1999;42:2021–34.CrossRefPubMed
19.
Parent EE, Carlson KE, Katzenellenbogen JA. Synthesis of 7α-(fluoromethyl)dihydrotestosterone and 7α-(fluoromethyl)nortestosterone, structurally paired androgens designed to probe the role of sex hormone binding globulin in imaging androgen receptors in prostate tumors by positron emission tomography. J Org Chem. 2007;72:5546–54.CrossRefPubMed
20.
Segaloff A. The enhanced local androgenic activity of 19-nor steroids and stabilization of their structure by 7α- and 17α-methyl substituents to highly potent androgens by any route of administration. Steroids. 1963;1:299–315.CrossRef
21.
Brandes SJ, Katzenellenbogen JA. Fundamental considerations in the design of fluorine-18 labeled progestins and androgens as imaging agents for receptor-positive tumors of the breast and prostate. Nucl Med Biol. 1988;15:53–67.
22.
Liu A, Carlson KE, Katzenellenbogen JA. Synthesis of high affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography. J Med Chem. 1992;35:2113–29.CrossRefPubMed
23.
Gunther JR, Parent AA, Katzenellenbogen JA. Alternative inhibition of androgen receptor signaling: peptidomimetic pyrimidines as direct androgen receptor/coactivator disruptors. ACS Chem Biol. 2009;19:430–40.
24.
Symes EK. Uptake and retention of androgens by the rat ventral prostate and consideration of their use as site directing agents. Biochem Pharmacol. 1982;31:3231–6.CrossRefPubMed
25.
Li C, Qiu W, Yang Z, Luo J, Yang F, Liu M, et al. Stereoselective synthesis of some methyl-substituted steroid hormones and their in vitro cytotoxic activity against human gastric cancer cell line MGC-803. Steroids. 2010;75:859–69.CrossRefPubMed
26.
Bastein D, Leblanc V, Asselin É, Bérubé G. First synthesis of separable isomeric testosterone dimers showing differential activities on prostate cancer cells. Bioorg Med Chem Lett. 2010;20:2078–81.CrossRef
27.
Tachibana K, Imaoka I, Yoshino H, Emura T, Kodama H, Furuta Y, et al. Discovery of 7α-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships. Bioorg Med Chem. 2007;15:174–85.CrossRefPubMed
28.
Okamoto M, Shibayama H, Naka K, Kitagawa Y, Ishiwata K, Shimizu I, et al. Optimization of the alkyl side chain length of fluorine-18-labeled alkyl-fluoroestradiol. Nucl Med Biol. 2016;43:512–9.CrossRefPubMed
29.
Yin H, Anders MW, Jones JP. Metabolism of 1,2-dichloro-1-fluoroethane and 1-fluoro-1,2,2-trichloroethane: electronic factors govern the regioselectivity of cytochrome P450-dependent oxidation. Chem Res Toxicol. 1996;9:50–7.CrossRefPubMed
30.
Kharasch ED, Thummel KE. Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurabe, isoflurane, and methoxyflurane. Anesthesiology. 1993;79:795–807.CrossRefPubMed
31.
Rasmussen MK, Zamaratskaia G, Ekstrand B. In vitro cytochrome P450 2E1 and 2A activities in the presence of testicular steroids. Reprod Domest Anim. 2011;46:149–54.CrossRefPubMed
Metadata
Title
Synthesis and basic evaluation of 7α-(3-[18F]fluoropropyl)-testosterone and 7α-(3-[18F]fluoropropyl)-dihydrotestosterone
Authors
Mayumi Okamoto
Kyosuke Naka
Kiichi Ishiwata
Isao Shimizu
Jun Toyohara
Publication date
01-01-2017
Publisher
Springer Japan
Published in
Annals of Nuclear Medicine / Issue 1/2017
Print ISSN: 0914-7187
Electronic ISSN: 1864-6433
DOI
https://doi.org/10.1007/s12149-016-1130-7

Other articles of this Issue 1/2017

Annals of Nuclear Medicine 1/2017 Go to the issue

Original Article

Cost-effective initial assessment strategies for thyroid nodules in iodine-adequate areas

Original Article

Low- and high-dose radioiodine therapy for low-/intermediate-risk differentiated thyroid cancer: a preliminary clinical trial

Original Article

Intratumoral heterogeneity of 18F-FLT uptake predicts proliferation and survival in patients with newly diagnosed gliomas

Original Article

Determination of radionuclides and radiochemical impurities produced by in-house cyclotron irradiation and subsequent radiosynthesis of PET tracers

Original Article

Sentinel-node mapping in endometrial cancer patients: comparing SPECT/CT, gamma-probe and dye

Original Article

Influence of volumetric 4′-[methyl-11C]-thiothymidine PET/CT parameters for prediction of the clinical outcome of head and neck cancer patients