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

Annals of Nuclear Medicine Aims and scope Submit manuscript

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.

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Acknowledgments

We thank Mr. Kunpei Hayashi (SHI Accelerator Service) and Mr. Masanari Sakai (SHI Accelerator Service) for their technical support with the cyclotron operation and radiosynthesis, and Dr. Mitsuo Umezu (Waseda University), Dr. Seijiro Hosokawa (Waseda University) and Dr. Shinji Takeoka (Waseda University) for their valuable advice. This work was supported in part by Japanese Society for the Promotion of Science Grant Nos. JP25293271 and JP 26870647, and an Early Bird support project for young researchers at Waseda Research Institute for Science and Engineering.

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Correspondence to Jun Toyohara.

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Funding

Japanese Society for the Promotion of Science Grant Nos. JP25293271 and JP26870647, and an Early Bird support project for young researchers at Waseda Research Institute for Science and Engineering.

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I. Shimizu: Deceased.

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Okamoto, M., Naka, K., Ishiwata, K. et al. Synthesis and basic evaluation of 7α-(3-[18F]fluoropropyl)-testosterone and 7α-(3-[18F]fluoropropyl)-dihydrotestosterone. Ann Nucl Med 31, 53–62 (2017). https://doi.org/10.1007/s12149-016-1130-7

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  • DOI: https://doi.org/10.1007/s12149-016-1130-7

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