Synthesis, in vivo rhesus monkey biodistribution and in vitro evaluation of a 11C-labelled potent aromatase inhibitor: [N-methyl-11C]vorozole.

[N-methyl-11C]Vorozole, a high-affinity aromatase-binding radiotracer, was synthesized through N-methylation of the corresponding nor-vorozole derivative using [11C]methyl iodide. [N-methyl-11C]Vorozole was obtained in 53-56% radiochemical yield based on [11C]methyl iodide within 40 min of the end of radionuclide production. The final formulation was >98% radiochemically pure and had a specific radioactivity of 10-143 GBq/micromol. In vitro, [N-methyl-11C]vorozole displayed high and specific binding to aromatase-rich human placenta. [N-methyl-11C]Vorozole binding to other tissues was lower and less specific. The dissociation constant measured was in the low nM range (Kd 1.7 nM), consistent with published Ki values for vorozole. Biodistribution studies in rhesus monkeys showed high liver uptake, which reached a constant level of 20% of the injected dose after 10 min, and an otherwise relatively even distribution of radioactivity. Pretreatment with vorozole only caused minor alterations of the biodistribution of the tracer.

Synthesis and in vitro evaluation of [carbonyl-11C]estramustine and [carbonyl-11C]estramustine phosphate.

[carbonyl-11C]Estramustine and [carbonyl-11C]estramustine phosphate were synthesized from [11C]phosgene using a one pot procedure. [carbonyl-11C]Estramustine was obtained in 31-43% decay corrected yield based on radioactivity trapped in the reaction vessel. The product was obtained 25 min after the end of radionuclide production with a specific radioactivity of 0.38-1.11 Ci/mumol. A method was developed yielding [carbonyl-11C]estramustine phosphate in 29-45% decay corrected yield based on trapped radioactivity, without purification of the [carbonyl-11C]estramustine intermediate. The product was obtained within 40 min of the end of radionuclide production with a specific radioactivity of 0.59-0.86 Ci/mumol. Results from in vitro experiments suggest that because of their high nonspecific binding, the compounds are unsuitable for positron emission tomography as imaging agents for the estramustine binding protein in cancer.

Synthesis of 11 beta-[18F]fluoro-5 alpha-dihydrotestosterone and 11 beta-[18F]fluoro-19-nor-5 alpha-dihydrotestosterone: preparation via halofluorination-reduction, receptor binding, and tissue distribution.

We have prepared 11 beta-fluoro-5 alpha-dihydrotestosterone (11 beta-F-DHT, 1) and 11 beta-fluoro-19-nor-5 alpha-dihydrotestosterone (11 beta-F-19-nor-DHT, 2) in order to investigate the properties of these new androgens labeled with fluorine-18 as potential androgen receptor (AR)-based imaging agents for prostate cancer. These compounds were synthesized in 6 steps from hydrocortisone and in 13 steps from 1,4-androstadiene-3,11,17-trione, respectively. Relative binding affinities (RBA) of 11 beta-F-DHT and 11 beta-F-19-nor-DHT to AR are 53.1 and 75.3 (R1881 = 100), respectively, the latter being the highest reported among fluorine-substituted androgens. The fluorination step, which involves addition of halogen fluoride across the 9(11)-double bond, followed by reductive dehalogenation at the 9 alpha-position has been adapted to introduce a fluorine-18-label at the 11 beta-position of DHT and 19-nor-DHT. The two high-affinity F-18-labeled ligands [18F]-1 and [18F]-2 were evaluated in vivo, in tissue distribution studies using diethylstilbestrol-pretreated mature male rats. 11 beta-F-DHT shows high prostate uptake and selective prostate to blood and prostate to muscle uptake ratios, the latter two ratios increasing from 5 and 8 at 1 h to 12 and 19 at 4 h postinjection. Moreover, this compound has low uptake in bone, displaying the lowest in vivo defluorination among all androgens labeled with fluorine-18 tested so far. The in vivo properties of 11 beta-F-DHT in rats are thus favorable for imaging of prostate cancer. On the other hand, 11 beta-F-19-nor-DHT shows low prostate uptake with low selectivity and high uptake in liver, kidney, and bladder. Even though this ligand has the highest RBA and undergoes little metabolic defluorination, it appears to suffer from rapid metabolism in vivo. Therefore, it is apparent that the biodistribution properties of androgens are affected by their structure and metabolism as well as by their RBA.