Download Synthesis of F-18 Fluoroestradiol (FES)

Synthesis of F-18 Fluoroestradiol (FES) T. J. Tewson
The routine synthesis of F-18 16α-fluoroestradiol (1), starting from the 3-methoxymethyl ether of
16α,17α-cyclic sulfate of estriol (2) will be discussed. There is an alternative synthesis in the literature
using the 3, 16-ditriflate of 16β-hydroxy estrone (3)[1]. We have no experience with this substrate and its
use will not be covered.
OH
18
O
O S O
O
F
O
OSO3
18
OSO2CF3
F
HO
CH3OCH2O
(1)
CF3SO2O
(2)
RO
(3)
(4)
.
The substrate is commercially available (ABX) but we have always made our own[2]. The synthesis is
straight forward provided that freshly distilled chloromethylmethyl ether is used to make 3methoxymethyl ether and that the final product is purified at the end of synthesis. The product should
have a M.Pt. of > 150ºC. Any residual imidazole, from the cyclic sulfate formation is hard to see and can
seriously interfere with the fluorination.
The fluorine-18 fluorination reaction is straight forward, using 10 micromoles (3 mg) and either tetrabutyl
ammonium carbonate or potassium carbonate/Kryptofix® under standard conditions.
Fluoride
incorporation yields are typically >90% and have exceeded 99%. Only one fluorination product is formed
under these conditions. If much less than 10 micromoles of starting material is used there is a second
radioactive product formed in very small amounts < 1%. The fluorination reaction can be monitored by
HPLC using a C-18 column and a 50% ethanol/water eluant with UV detection at 284 nm. In our hands
reverse phase chromatography of the intermediate sulfate salt (4), the product of the fluorination reaction,
is much improved if the column has been pretreated with ammonium acetate solution.
Acid hydrolysis of the 3-methoxymethyl ether is straight forward but removal of the 17α-sulfate is more
difficult. The hydrolysis is an acid catalyzed reaction but the rate of hydrolysis is not a function of acid
strength. It is faster in non-aqueous media but it is not any cleaner. Only one major product is formed,
the required FES (1) but an HPLC of the reaction mixture shows an elevated, lumpy baseline suggesting
that many minor products are formed. We have hydrolysed the sulfate in 0.1 N HCl at 140ºC in a sealed
vial for 30 minutes which gives total cleavage of both the sulfate and the methoxy methyl ether. Others
have done the hydrolysis in 0.1 N HCl in acetonitrile and this apparently works well[3]. The final product
is purified by prep HPLC on C-18 column using 1:1 EtOH/water as the eluant. Under our conditions the
product comes of the column in about 5mls. This is then diluted with PBS so as to bring the final ethanol
concentration of the final product to < 10%. However before the solution is diluted it must be kept away
from plastic containers. The 50% ethanol solution will wash small amounts of the plasticizer nonyl
phenol from the plastic. Nonyl phenol is mildly estrogenic and inclusion of it in the final product will
lower the effective specific activity of the FES. The chemical specific activity of the product follows that
of the F-18 fluoride, as would be predicted. The final yield, starting from 150 mCi’s of F-18 fluoride is
typically 30 mCi’s with a synthesis time of ~ 2 hours.
1.
2.
3.
Katzenellenbogen, J.A., M.J. Welch, and F. Dehdashti, The development of estrogen and progestin
radiopharmaceuticals for imaging breast cancer. Anticancer Research, 1997. 17(3B): p. 1573-6.
Lim, J.L., et al., The use of 3-methoxymethyl-16 beta, 17 beta-epiestriol-O-cyclic sulfone as the
precursor in the synthesis of F-18 16 alpha-fluoroestradiol. Nucl Med Biol, 1996. 23(7): p. 911-5.
Romer, J., et al., Automated production of 16alpha-[18F]fluoroestradiol for breast cancer
imaging. Nuclear Medicine & Biology, 1999. 26(4): p. 473-9.