title: Synthesis, estrogen receptor binding, and tissue distribution of a new iodovinylestradiol derivative (17alpha,20E)-21-[123I]Iodo-11beta-nitrato-19-norp regna-1,3,5 (10),20-tetraene-3,17-diol (E-[123I]NIVE).
abstract: We have synthesized and evaluated E-11beta-nitrato-17alpha-iodovinylestradiol (E-NIVE; E-3c) and its 123I-labelled form, as a new potential radioligand for imaging of estrogen receptor (ER)-positive human breast tumors. E-[123I]NIVE was prepared by stereospecific iododestannylation of the E-tri-n-butylstannylvinyl precursor (E-2c), obtained from reaction of 11beta-nitrato-estrone (8) with E-tributylstannylvinyllithium. In competitive binding studies, E-NIVE proved to have high binding affinity for both the rat and the human ER (Ki 280-730 pM), without significant binding to human sex hormone binding globulin. Distribution studies in normal and mammary tumor-bearing rats showed specific ER-mediated uptake of E-[123I]NIVE in the estrogen target tissues, i.e., uterus, ovaries, pituitary, and hypothalamus, but not in the mammary tumors. Selective retention in these target tissues, including tumor tissue, resulted in significant increases over time for the target tissue-to-muscle uptake ratios, but not for the target tissue-to-fat uptake ratios. The tumor-to-fat uptake ratio even appeared constantly below 1. In the primary estrogen target tissues, E-[123I]NIVE displayed high specific ER-mediated uptake and retention, which resulted in moderate target-to-nontarget tissue uptake ratios. In contrast, in tumor tissue, E-[123I]NIVE uptake appeared to be rather low and not ER-specific. As a consequence, E-[123I]NIVE appears to be a less favorable radioligand for ER imaging in breast cancer than the previously studied stereoisomers of 11beta-methoxy-17alpha-[123I]iodovinylestradiol (E- and Z-[123I]MIVE; [123I]E- and [123I]Z-3b).
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: L J
authors.initials: LJ
authors.lastname: Rijks
authors.forename: J C
authors.initials: JC
authors.lastname: van den Bos
authors.forename: P A
authors.initials: PA
authors.lastname: van Doremalen
authors.forename: G J
authors.initials: GJ
authors.lastname: Boer
authors.forename: K
authors.initials: K
authors.lastname: de Bruin
authors.forename: T
authors.initials: T
authors.lastname: Doornbos
authors.forename: J A
authors.initials: JA
authors.lastname: Vekemans
authors.forename: M A
authors.initials: MA
authors.lastname: Posthumus
authors.forename: A G
authors.initials: AG
authors.lastname: Janssen
authors.forename: E A
authors.initials: EA
authors.lastname: van Royen
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000000981:diagnostic imaging; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014407:Tumor Cells, Cultured
chemical_list: C114152:21-iodo-11-nitrato-19-norpregna-1,3,5(10),20-tetraene-3,17-diol; D007457:Iodine Radioisotopes; D011960:Receptors, Estrogen; D012738:Sex Hormone-Binding Globulin; D004958:Estradiol