Synthesis and evaluation of fluorine-18 labeled androgens as in vivo imaging agents for prostatic cancer using PET

In order to develop androgen receptor (AR) based probes for in vivo imaging of prostatic cancer using positron emission tomography (PET), four pairs of 16$\beta$- and 16$\alpha$-fluoro androgens, as well as two 20-fluoro androgens have been synthesized. The fluorination was achieved mainly by nucleophilic fluoride displacement of a triflate or a spirocyclic sulfate precursor, prepared by multistep synthesis.Of the ten fluorinated androgens, 16$\beta$-F-DHT (1), 16$\beta$- and 16$\alpha$-F-Mib (5 and 6), 16$\beta$- and 16$\alpha$-F-MNT (7 and 8), 20-F-Mib (9), as well as 20-F-R1881 (10) were found to have high relative binding affinity for AR, 19%-53% of the potent androgen R1881. In most cases, the fluorination improved the binding selectivity of the androgens to AR vs. other steroid receptors and SBP, and the 16$\beta$-fluoro androgens have higher affinity than their corresponding 16$\alpha$-fluoro epimers. Other interesting structure-activity relationships were observed.Seven of these fluorinated androgens have been prepared in fluorine-18 labeled form, and their in vivo tissue distribution have been studied in estrogen-treated mature male rats. All seven fluorine-18 labeled androgens showed selective and blockable target tissue uptake: the prostate to blood and prostate to muscle ratios (at 4 h) were from 5 (20-F-R1881) to 30 (16$\alpha$-F-MNT), and the uptake in the unblocked animals were 2.5 (16$\beta$-F-Mib) to 5.3 (16$\alpha$-F-MNT and 20-F-MIb) fold higher than that in the blocked animals. Rapid in vivo defluorination was observed with three 16$\beta$-fluoro androgens (1, 3 and 7). Thus, we have synthesized the first fluorine-18 labeled androgens that have relative high binding affinity and selectivity for AR, and show selective target tissue uptake. It appears that 16$\beta$-F-F-Mib (5), 16$\alpha$-F-MNT (8) and 20-F-Mib (9) are the most promising candidates as in vivo imaging agents for prostatic cancer.U of I OnlyETDs are only available to UIUC Users without author permissio