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Title:Rhenium and technetium-labeled progestins, the development of receptor-directed agents for diagnostic imaging or therapy
Author(s):DiZio, James Patrick
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Organic
Chemistry, Pharmaceutical
Chemistry, Radiation
Abstract:In order to investigate the possibility of developing diagnostic imaging agents for steroid receptor-positive tumors that are labeled with the readily available radionuclide technetium-99m, three conjugate systems have been prepared in which a progestin is linked to a metal chelate system. These are bis-amino bis-thiol (BAT or N$\sb2$S$\sb2$) systems and are linked through carbon-21 of progesterone or the 17$\alpha$- or 11$\beta$-position of a nortestosterone type progestin. As a model for technetium-labeled complexes, all three chelate systems were converted to their oxo-rhenium complexes. Of the four possible diastereomeric products in each of these systems, a syn pair and an anti pair (linker methylene vs. rhenium-oxo, relative to the N$\sb2$S$\sb2$ plane) were separated in the 17$\alpha$-substituted series (B6syn1,2 and B6anti1,2), a syn pair was isolated in the 21-substituted series (A4syn1,2), and a syn pair and the two individual anti diastereomers were separated in the 11$\beta$-substituted series (C15syn1,2, C15anti1, and C15anti2). In competitive radiometric receptor binding assays, the 21-, and 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 11$\beta$-linked syn system was also prepared in Tc-99 labeled form (5). The two anti diastereomers (5anti1 and 5anti2) had affinities of 7% and 47%, and the syn pair (5syn1,2) had an affinity of 25% relative to R5020. The latter findings indicate that it is possible to prepare metal-labeled steroids that retain high affinity for steroid receptors. Tc-99m and Re-186 analogs of the 11$\beta$-linked syn system were then prepared (6 and 7). In vitro studies of the Tc-99m and Re-186 systems showed that the conjugates bind with the metal-oxo core intact and that the specific to non-specific binding ratios for the Tc-99m and Re-186 analogs are 75/25 and 54/46, respectively. In vivo, conjugates 6 and 7 showed receptor mediated uptake in rat uterus but also high uptake in non-target tissues. The high lipophilicity of the chelates is presumed to be the reason for the large non-selective binding. Modified, less lipophilic systems, may be useful in vivo as receptor directed agents for diagnostic imaging or treatment of steroid receptor-positive tumors.
Issue Date:1991
Rights Information:Copyright 1991 DiZio, James Patrick
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9210785
OCLC Identifier:(UMI)AAI9210785

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