Annals of nuclear medicine

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

PMID 27680022


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-[(18)F]fluoropropyl)-testosterone ([(18)F]7) and 7α-(3-[(18)F]fluoropropyl)-dihydrotestosterone ([(18)F]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats. We synthesized [(18)F]7 and [(18)F]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-(3)H]-methyltrienolone ([(3)H]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 (36xa0µg/animal). 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 (13.0xa0±xa03.3xa0nM) was higher than 7 (47.8xa0±xa010.0xa0nM). In contrast to the AR binding affinity, the ventral prostate uptake of [(18)F]7 and [(18)F]15 at 2xa0h post-injection was similar (0.07xa0% injected dose/g of tissue). A blocking study indicated that specific binding of [(18)F]15 is observed in the ventral prostate. [(18)F]7 and [(18)F]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents. [(18)F]15 is better than [(18)F]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 [(18)F]15 in prostate might be insufficient for in vivo visualization. Although [(18)F]7 and [(18)F]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16β-[(18)F]fluoro-5α-dihydrotestosterone. It is also revealed that the shorter side chain length of 7α-[(18)F]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [(18)F]15, in terms of net prostate uptake and in vivo metabolic stability.

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R1881, ≥98% (HPLC)