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

7 alpha-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized fluoropropyl derivatives of 7 alpha-(3-[F-18]fluoropropyl)-testosterone ([F-18]7) and 7 alpha-(3-[F-18]fluoropropyl)-dihydrotestosterone ([F-18]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats. We synthesized [F-18]7 and [F-18]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 [17 alpha-methyl-H-3]-methyltrienolone ([H-3]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 A mu g/animal). 7 alpha-(3-Fluoropropyl)-testosterone (7) and 7 alpha-(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 [F-18]7 and [F-18]15 at 2 h post-injection was similar (0.07 % injected dose/g of tissue). A blocking study indicated that specific binding of [F-18]15 is observed in the ventral prostate. [F-18]7 and [F-18]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents. [F-18]15 is better than [F-18]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 [F-18]15 in prostate might be insufficient for in vivo visualization. Although [F-18]7 and [F-18]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16 beta-[F-18]fluoro-5 alpha-dihydrotestosterone. It is also revealed that the shorter side chain length of 7 alpha-[F-18]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [F-18]15, in terms of net prostate uptake and in vivo metabolic stability.