Issue 20, 2002

Synthesis of 16α-fluoro ICI 182,780 derivatives: powerful antiestrogens to image estrogen receptor densities in breast cancer by positron emission tomography

Abstract

We prepared a new series of 7α-substituted derivatives of 16α-fluoroestradiol, based on the very potent antiestrogen 7α-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}-estra-1,3,5(10)-triene-3,17β-diol (ICI 182,780; Faslodex™). The latter consist of estradiol functionalized with a side chain at the 7α-position, conferring interesting pharmaceutical properties for endocrine therapy of estrogen receptor (ER) positive breast cancer. The considerable advantages of ICI 182,780 over other selective ER-modulators (SERMs) already used in hormonal therapy, lead us to develop three new 16α-fluoro derivatives with potential use in positron emission tomography (PET), for the imaging of ER densities in breast tumors. Introduction of the long side chain at the 7α-position was accomplished by Cu(I)-promoted conjugate addition of a Grignard reagent to 6-dehydro-19-nortestosterone. Subsequent oxidation of the 17-hydoxy group and A-ring aromatization gave a 7α-substituted estrone derivative. Further addition to complete the side chain gave the ICI 182,780 mimics that were converted to the reactive 16β,17β-cyclic sulfates, i.e. the key intermediates for the 18F-labeling reaction. Opening of the cyclic sulfates via nucleophilic fluorination with Me4NF, followed by rapid hydrolysis in acidic ethanol of the protecting ether and sulfate groups, yielded the desired 16α-fluoro PET derivatives of ICI 182,780. The latter procedure is readily adapted for radiolabeling with 18F by substituting Me4NF for 18F in acetonitrile.

Graphical abstract: Synthesis of 16α-fluoro ICI 182,780 derivatives: powerful antiestrogens to image estrogen receptor densities in breast cancer by positron emission tomography

Article information

Article type
Paper
Submitted
10 Jun 2002
Accepted
15 Aug 2002
First published
20 Sep 2002

J. Chem. Soc., Perkin Trans. 1, 2002, 2275-2281

Synthesis of 16α-fluoro ICI 182,780 derivatives: powerful antiestrogens to image estrogen receptor densities in breast cancer by positron emission tomography

Y. Seimbille, F. Bénard and J. E. van Lier, J. Chem. Soc., Perkin Trans. 1, 2002, 2275 DOI: 10.1039/B205571F

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