title: Progestin-rhenium complexes: metal-labeled steroids with high receptor binding affinity, potential receptor-directed agents for diagnostic imaging or therapy.
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.
authors.affiliation: Department of Chemistry, University of Illinois, Urbana 61801.
authors.forename: J P
authors.initials: JP
authors.lastname: DiZio
authors.forename: R
authors.initials: R
authors.lastname: Fiaschi
authors.forename: A
authors.initials: A
authors.lastname: Davison
authors.forename: A G
authors.initials: AG
authors.lastname: Jones
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D004092:20-alpha-Dihydroprogesterone / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents; D002614:Chelating Agents / Q000737:chemistry; D003952:Diagnostic Imaging; D007553:Isotope Labeling; D009277:Nandrolone / Q000737:chemistry / Q000378:metabolism; D009644:Norgestrel / Q000737:chemistry / Q000378:metabolism; D011372:Progestins / Q000737:chemistry* / Q000627:therapeutic use; D011980:Receptors, Progesterone / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry*; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D011372:Progestins; D011980:Receptors, Progesterone; D013438:Sulfhydryl Compounds; D004092:20-alpha-Dihydroprogesterone; D009644:Norgestrel; D009277:Nandrolone; D012211:Rhenium