18F-labeled difluoroestradiols: preparation and preclinical evaluation as estrogen receptor-binding radiopharmaceuticals

Steroids. 2002 Aug;67(9):765-75. doi: 10.1016/s0039-128x(02)00025-9.


A-ring fluorination of estradiol (ES) at position 2 or 4 decreases the rate of metabolism by blocking the formation of catechol estrogens, one of the major metabolic pathways of ES. We postulate that adding a 2- or 4-fluoro substituent to 16alpha-[18F]fluoroestradiol (FES), a positron emission tomography (PET) radiopharmaceutical used for estrogen receptor (ER) imaging, should prolong its blood circulation time, and thus, improve its localization in ER-rich target tissues. On such account, we prepared a series of FES derivatives substituted with a fluorine atom at C2 or C4, with or without an 11beta-OMe group, and we tested their binding affinities for the ER and different serum proteins including rat alphafetoprotein (AFP) and human sex hormone-binding globulin (SHBG). Labeling at the 16alpha-position was accomplished via nucleophilic substitution with [18F]F(-) on the reactive 16beta,17beta-cyclic sulfate intermediates. Decay corrected yields varied between 30 and 50% for a total synthesis time of 120 min, providing final products with specific activities >3000 Ci/mmol. The 18F-labeled analogs were evaluated for their biodistribution in immature female rats. Substitutions with the 4-F have little effect on binding affinities. Addition of the 2-F diminishes ER and AFP-binding affinities while augmenting the affinity for the SHBG. Addition of the 11beta-OMe decreases all binding affinities, particularly to AFP and SHBG. In contrast, biodistribution of the corresponding [16alpha-18F]fluoro analogs in immature female rats revealed that the presence of the 11beta-OMe group improves ER-mediated uterus uptake, with the 4,16alpha-[16alpha-18F]difluoro-11beta-methoxyestradiol showing the highest uptake values (15% ID at 1-h post-injection). These data suggest that the addition of both a 4-F and 11beta-OMe group onto FES may provide an improved radiopharmaceutical for PET imaging of ER densities in breast cancer patients.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / diagnostic imaging
  • Estradiol / analogs & derivatives*
  • Estradiol / chemical synthesis
  • Estradiol / chemistry
  • Estradiol / metabolism*
  • Female
  • Fluorine Radioisotopes*
  • Humans
  • Isotope Labeling
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / metabolism*
  • Sex Hormone-Binding Globulin / metabolism
  • Thermodynamics
  • Tomography, Emission-Computed / methods
  • alpha-Fetoproteins / metabolism


  • Fluorine Radioisotopes
  • Radiopharmaceuticals
  • Receptors, Estrogen
  • Sex Hormone-Binding Globulin
  • alpha-Fetoproteins
  • Estradiol