Rhenium and technetium-labeled progestins, the development of receptor-directed agents for diagnostic imaging or therapy

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 17α- or 11β-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 17α-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 11β-substituted series (C15syn1,2, C15anti1, and C15anti2). In competitive radiometric receptor binding assays, the 21-, and 17α-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 11β-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 11β-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 11β-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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2011

Author dc:creator

• DiZio, James Patrick

• Chemistry, Organic
• Chemistry, Pharmaceutical
• Chemistry, Radiation

Statement dc:rights

• Copyright 1991 DiZio, James Patrick

Language dc:language

eng

Identifier

(UMI)AAI9210785
AAI9210785

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/19195