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

To improve the pharmacokinetics of fluorine-18 labeled estrogens to be used as receptor-based imaging agents for the identification and staging of estrogen-receptor-positive breast carcinoma, we wanted to synthesize 2- [¹⁸F]fluoroestradiol. This compound has high affinity for the estrogen receptor and 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 reduced uptake in the liver. The synthesis of a [¹⁸F]fluoroaryl estrogen at the high specific activity, no-carrier-added level requires the use of [¹⁸F]Fas a precursor. Several strategies were explored for the synthesis of a [¹⁸F]fluoroaryl estrogen. The synthesis of 2- [¹⁸F]fluoroestradiol was eventually achieved by [¹⁸F]fluoride ion displacement of a trimethylammonium leaving group at C-2 of an estrogen, with additional activation being provided by a 6-keto group which was subsequently removed by reduction. Incorporation yields of fluorine-18 were between 20% and 50%. The potential of this new radiopharmaceutical as an imaging agent is being evaluated in an appropriate animal model.