Preparation and evaluation of 17-ethynyl-substituted 16 alpha-[18F]fluoroestradiols: selective receptor-based PET imaging agents

Int J Rad Appl Instrum B. 1992 Apr;19(3):363-74. doi: 10.1016/0883-2897(92)90122-f.

Abstract

We have prepared and studied six new analogs of 16 alpha-fluoroestradiol (FES): 17 alpha- and 17 beta-ethynyl-FES (7 [FEES] and 7a), and the 11 beta-ethyl (8 and 8a) and 11 beta-methoxy (9 and 9a) derivatives, novel estrogen receptor-based PET imaging agents. The relative binding affinity (RBA) for the estrogen receptor (ER) versus FES is increased for 7, 9 and 9a but decreased for 7a, 8 and 8a. All six analogs have been labeled in the 16 alpha position with 18F by the nucleophilic displacement of the corresponding 16 beta-trifluoromethanesulfonate with nBu4N18F. Subsequent ethynylation with lithium trimethylsilylacetylide yielded the FEES analogs (total synthesis time: 120 min; effective specific activity: 200-2400 Ci/mmol). Selective uptake in the uterus was high for [18F]7, [18F]8, [18F]9 and [18F]9a (% ID/g values at 1 h: 11.2, 12.9, 9.9 and 8.3, respectively), while uptake was effectively blocked by coinjection of an excess of unlabeled estradiol. The FEES analogs, [18F]7, [18F]8 and [18F]9, exhibited the highest selectivity, in terms of target (uterus)-to-blood ratios, ever seen amongst estrogen radiopharmaceuticals, 154, 145 and 169, respectively. The analogs [18F]7a and [18F]8a displayed no uptake in the uterus, consistent with their low RBAs. Metabolism studies revealed that most of the uterine activity is unmetabolized while the blood exhibits a rapid and subsequently sustained mixture of metabolites. The muscle shows a metabolic profile intermediate to the uterus and blood. These analogs provide an array of desirable characteristics for the optimal PET imaging of ER-rich target tissues.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Proteins / metabolism
  • Carrier Proteins / metabolism
  • Estradiol / analogs & derivatives*
  • Estradiol / chemical synthesis
  • Estradiol / metabolism
  • Estradiol / pharmacokinetics
  • Female
  • Fluorine Radioisotopes*
  • Muscles / metabolism
  • Protein Binding
  • Rats
  • Rats, Inbred Strains
  • Receptors, Estrogen / analysis
  • Receptors, Estrogen / metabolism
  • Tissue Distribution
  • Tomography, Emission-Computed
  • Uterus / metabolism

Substances

  • Blood Proteins
  • Carrier Proteins
  • Fluorine Radioisotopes
  • Receptors, Estrogen
  • Estradiol
  • 16-fluoroestradiol
  • 17-ethynyl-16-fluoroestradiol