Synthesis, estrogen receptor binding, and tissue distribution of [18F]fluorodoisynolic acids

Andrew W. Scribner, Stephanie D. Jonson, Michael J. Welch, John A. Katzenellenbogen

Research output: Contribution to journalArticlepeer-review


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 14α-hydrogen configuration, trans- FDA) and the more active cis-doisynolic acid (with the unnatural 14β- hydrogen configuration, cis-FDA) from estrone and 14β-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.

Original languageEnglish (US)
Pages (from-to)209-224
Number of pages16
JournalNuclear Medicine and Biology
Issue number3
StatePublished - Apr 1997


  • Doisynolic acid
  • Estrogen receptor
  • Estrogens
  • Fluorine-18
  • Uterus

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research


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