Progestin-rhenium complexes: metal-labeled steroids with high receptor binding affinity, potential receptor-directed agents for diagnostic imaging or therapy

Bioconjug Chem. 1991 Sep-Oct;2(5):353-66. doi: 10.1021/bc00011a011.

Abstract

In order to investigate the possibility of developing diagnostic imaging agents for steroid-positive tumors that are labeled with the readily available radionuclide technetium-99m, we prepared four conjugate systems in which a progestin is linked to a metal chelate system. Three of these are bis-amino bis-thiol (BAT or N2S2) systems and are linked through carbon-21 of progesterone or the 17 alpha- or 11 beta-position of a nortestosterone type progestin. The fourth, an amino-amido-thiol-alcohol chelate (N2OS) system, is linked at the 16 alpha,17 alpha-positions of a dihydroprogesterone. As a model for technetium-labeled complexes, all four chelate systems were converted to their oxo-rhenium complexes. Of the four possible diastereomers in the 16 alpha,17 alpha-system, only one was isolated, while of the four possible diastereomers in the other systems, a syn pair and an anti pair (linker methylene vs rhenium-oxo, relative to the N2S2 plane) were separated in the 17 alpha-substituted series, a syn pair was isolated in the 21-substituted series, and a syn pair and the two individual anti diastereomers were separated in the 11 beta-substituted series. In competitive radiometric receptor binding assays, the 21-, 17 alpha-, and 16 alpha,17 alpha-linked systems had low affinity for the progesterone receptor (less than 0.3% that of promegestone (R5020) or 2% that of progesterone). By contrast, the two anti diastereomers of the 11 beta-linked system had affinities that were 10% and 44% that of R5020 (or 64% and 283% that of progesterone) and the syn pair had an affinity 25% that of R5020 (or 161% that of progesterone). The latter finding indicates that it is possible to prepare metal-labeled steroids that retain high affinity for steroid receptors. These and related systems, when complexed with radioactive metals, may be useful in vivo as receptor-directed agents for diagnostic imaging or therapy of steroid receptor-positive tumors.

Publication types

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

MeSH terms

  • 20-alpha-Dihydroprogesterone / chemistry
  • 20-alpha-Dihydroprogesterone / metabolism
  • Antineoplastic Agents*
  • Chelating Agents / chemistry
  • Diagnostic Imaging*
  • Isotope Labeling
  • Nandrolone / chemistry
  • Nandrolone / metabolism
  • Norgestrel / chemistry
  • Norgestrel / metabolism
  • Progestins / chemistry*
  • Progestins / therapeutic use
  • Receptors, Progesterone / metabolism*
  • Rhenium / chemistry*
  • Stereoisomerism
  • Sulfhydryl Compounds / chemistry

Substances

  • Antineoplastic Agents
  • Chelating Agents
  • Progestins
  • Receptors, Progesterone
  • Sulfhydryl Compounds
  • 20-alpha-Dihydroprogesterone
  • Norgestrel
  • Nandrolone
  • Rhenium