title: Synthesis, estrogen receptor binding, and tissue distribution of [18F]fluorodoisynolic acids.
abstract: Doisynolic acids, D-ring seco-steroids derived from alkaline fusion of estrones, are hormonal curiosities: Their binding affinity for the estrogen receptor is low (ca. 1-2% that of estradiol), but their in vivo potency is high and they have a long duration of action. To study the in vivo behavior of the doisynolic acids, we prepared fluorine-substituted analogs of both trans-doisynolic acid (with the natural 14 alpha-hydrogen configuration, trans-FDA) and the more active cis-doisynolic acid (with the unnatural 14 beta-hydrogen configuration, cis-FDA) from estrone and 14 beta-estrone, respectively. Modification of the D-ring haloform cleavage approach of Meyers allowed us to introduce fluorine (or fluorine-18) on the carbon atom derived from C-16 in the estrones. Fluorine substitution had little effect on the estrogen receptor binding affinity of the doisynolic acids. Tissue distribution of the fluorodoisynolic acids (trans-[18F]FDA and cis-[18F]FDA) was unusual and very different from that of typical, high-affinity ligands for the estrogen receptor. At 1-3 h in immature female rats, trans-[18F]FDA shows low and rather nonselective uptake in the principal estrogen target tissue (uterus) and slow clearance. By contrast, cis-[18F]FDA shows high uptake in nearly all tissues, with significant uterine uptake that continues to increase over the 1-6-h period. The uterine uptake of this isomer was blocked at the later times by a sufficiently high dose of unlabeled cis-FDA. After administration of the trans-[18F]FDA, a more polar metabolite slowly accumulates in the blood. The cis-[18F]FDA, however, showed no apparent metabolism, with 84% of the blood activity at 5 h assigned as the unmetabolized radioligand. After 5 h, only limited clearance from blood, liver, and kidneys has occurred. No metabolite from this isomer accumulates in the uterus. Although fluorodoisynolic acids will not be useful breast-tumor imaging agents, their behavior was found to be interesting as it deviates from that of other F-18 estrogens. Further long-term studies of cis-doisynolic acid, labeled with tritium, may be needed to explicate fully its unusual distribution properties and high in vivo activity.
authors.affiliation: Department of Chemistry, University of Illinois, Urbana 61801, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Scribner
authors.forename: S D
authors.initials: SD
authors.lastname: Jonson
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D000818:Animals; D001711:Biotransformation; D005260:Female; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D012632:Secosteroids / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014599:Uterus / Q000000981:diagnostic imaging / Q000378:metabolism
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen; D012632:Secosteroids