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

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.

http://ift.tt/2d5BICc