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^-

Abstract

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-[(18)F]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 [(18)F]fluoroaryl estrogen at the high specific activity, no-carrier-added level requires the use of [(18)F]F(-) as a precursor. Several strategies were explored for the synthesis of a [(18)F]fluoroaryl estrogen. The synthesis of 2-[(18)F]fluoroestradiol was eventually achieved by [(18)F]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.

4-[18F]Fluoro-m-hydroxyphenethylguanidine: A Radiopharmaceutical for Quantifying Regional Cardiac Sympathetic Nerve Density with Positron Emission Tomography

“…Many methods have been developed for the incorporation of fluorine-18 into a deactivated electron-rich aromatic ring by a nucleophilic aromatic substitution reaction. 13–16 Recently, the use of diaryliodonium salts has received considerable attention as a one-step method of introducing fluorine-18 into ring structures with high radiochemical yields in electron-rich aromatic systems. 17–21 This approach provides specific activities that are sufficiently high for successful PET imaging studies of receptors in various organs.…”

Micropollutant sorption to membrane polymers: A review of mechanisms for estrogens

“…H-bonding has been attributed to play a predominant factor in the transport of estrogens in biological systems [37][38][39][40][41][42]. The hormones such as E1, E2 and DES all possess a phenol group which is electron rich [43] and can therefore have the potential to form π-π bonding with electron deficient phenyl groups [30] of the polymers.…”

Competitive demethylation and substitution in N,N,N-trimethylanilinium fluorides

“…If electron-withdrawing groups less potent than cyano are present on the trimethylanilinium ring, radiofluorination yields begin to decline. Corrected radiofluorination yields for para-trimethylammonium aryl aldehydes [24][25][26][27], ketones [28][29][30][31][32], and esters [33][34][35][36] range from excellent (80%) for aryl aldehydes to fair (50%) for aryl esters. For relatively unactivated rings, fluorodeamination is difficult; Ermert and coworkers [37] studied substitution in 4-bromo-N,N,N-trimethylanilinium triflates and found that only 8-12% yields of the desired 4-fluorobromobenzenes were obtained under optimized conditions.…”

“…Formation of [ 18 F] methyl fluoride has been observed in some cases where it is suspected to be the main deleterious side reaction [11,28]. The reverse Menschutkin reaction was also exploited for the preparation of labeled methyl fluoride; 2-acetyl-N,N,N-trimethylanilinium triflate readily undergoes microwave-induced [ 18 F] fluorodemethylation [39].…”