title: Impact on estrogen receptor binding and target tissue uptake of [18F]fluorine substitution at the 16alpha-position of fulvestrant (faslodex; ICI 182,780).
abstract: Fulvestrant (Faslodex; ICI 182,780) is a pure estrogen receptor (ER) antagonist recently approved for the treatment of hormone-sensitive breast cancer in post-menopausal women with disease progression following antiestrogen therapy. Fulvestrant strongly binds to the ER and its mode of action consists of inhibition of ER dimerization leading to a down regulation of ER protein cellular levels. With the aim to develop a probe for positron emission tomography (PET) imaging capable of predicting the potential therapeutic efficacy of selective ER modulators (SERM), we prepared three new 16alpha-[18F]fluoro-fulvestrant derivatives. These new radiopharmaceuticals were evaluated for their binding affinity to the human ERalpha and for their target tissue uptake in immature female rats. Substitution of one of the side-chain F-atoms of fulvestrant for 18F would have led to a product of low specific activity; instead we selected the 16alpha-position for 18F-labeling, which at least in the case of estradiol (ES) is well tolerated by the ER. Radiochemical synthesis proceeds by stereoselective introduction of the [18F]fluoride at the 16-18F-position of fulvestrant via opening of an intermediate O-cyclic sulfate followed by hydrolysis of the protecting methoxymethyl (MOM) ether and sulfate groups. Three analogs with different oxidation states of the side chain sulfur, i.e. sulfide, sulfone or sulfoxide (fulvestrant) were prepared. Introduction of the 16(18)F-fluorine led to a dramatic decrease of the apparent binding affinity for ER, as reported by Wakeling et al. (Cancer Res. 1991;51:3867-73). Likewise, in vivo ER-mediated uterus uptake values in immature female rats were disappointing. Overall, our findings suggest that these new PET radiopharmaceuticals are not suitable as tracers to predict ER(+) breast cancer response to hormonal therapy with selective ER modulators.
authors.affiliation: Sherbrooke PET Center, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4.
authors.forename: Yann
authors.initials: Y
authors.lastname: Seimbille
authors.forename: François
authors.initials: F
authors.lastname: Bénard
authors.forename: Jacques
authors.initials: J
authors.lastname: Rousseau
authors.forename: Emilie
authors.initials: E
authors.lastname: Pepin
authors.forename: Antonio
authors.initials: A
authors.lastname: Aliaga
authors.forename: Guillaume
authors.initials: G
authors.lastname: Tessier
authors.forename: Johan E
authors.initials: JE
authors.lastname: van Lier
mesh_terms: D000818:Animals; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D020847:Estrogen Receptor Modulators / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes; D000077267:Fulvestrant; D007202:Indicators and Reagents; D007553:Isotope Labeling; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D013431:Sulfates / Q000737:chemistry; D014018:Tissue Distribution; D014599:Uterus / Q000000981:diagnostic imaging / Q000378:metabolism
chemical_list: D020847:Estrogen Receptor Modulators; D005462:Fluorine Radioisotopes; D007202:Indicators and Reagents; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen; D013431:Sulfates; D000077267:Fulvestrant; D004958:Estradiol