Synthesis of 2-[F-18]fluoroestradiol, a potential diagnostic imaging agentfor breast cancer: Strategies to achieve nucleophilic substitution of an electron-rich aromatic ring with [F-18]F-

To improve the pharmacokinetics of fluorine-18 labeled estrogens to be used as receptor-based imaging agents for the identification and staging of est rogen-receptor-positive breast carcinoma, we wanted to synthesize 2-[F-18]f luoroestradiol. This compound has high affinity for the estrogen receptor a nd also binds very well to sex hormone binding globulin, a protein thought to protect estrogens from metabolism and deliver them to target tissues. We anticipated that this compound might have increased tumor uptake and reduc ed uptake in the liver. The synthesis of a [F-18]fluoroaryl estrogen at the high specific activity, no-carrier-added level requires the use of [F-18]F - as a precursor. Several strategies were explored for the synthesis of a [ F-18]fluoroaryl estrogen. The synthesis of 2-[F-18]fluoroestradiol was even tually achieved by [F-18]fluoride ion displacement of a trimethylammonium l eaving group at C-2 of an estrogen, with additional activation being provid ed by a 6-keto group which was subsequently removed by reduction. Incorpora tion yields of fluorine-18 were between 20% and 50%. The potential of this new radiopharmaceutical as an imaging agent is being evaluated in an approp riate animal model.