Rhenium and technetium-labeled progestins, the development of receptor-directed agents for diagnostic imaging or therapy
DiZio, James Patrick
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Permalink
https://hdl.handle.net/2142/19195
Description
Title
Rhenium and technetium-labeled progestins, the development of receptor-directed agents for diagnostic imaging or therapy
Author(s)
DiZio, James Patrick
Issue Date
1991
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Chemistry, Pharmaceutical
Chemistry, Radiation
Language
eng
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.
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