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(UMI)AAI9210785 DiZio, James Patrick 2011-05-07T11:59:49Z 2011-05-07T11:59:49Z 10000-01-01 1991 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. Made available in DSpace on 2011-05-07T11:59:49Z (GMT). No. of bitstreams: 2 license.txt: 4922 bytes, checksum: 910b249b4beec47e7ab768910c8f966f (MD5) 9210785.pdf: 4647309 bytes, checksum: b78f1e5d5733345fa8e09aa0adeb7717 (MD5) Previous issue date: 1991 Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by Howard Ding (hding2@illinois.edu) on 2011-05-07T14:35:18Z Item is restricted indefinitely. Restriction data tranferred 2014-07-01T11:13:52-05:00 Original Data Group with Access UIUC Users [automated] Release Date: none Reason: ETDs are only available to UIUC Users without author permission ETDs are only available to UIUC Users without author permission U of I Only AAI9210785 http://hdl.handle.net/2142/19195 eng Copyright 1991 DiZio, James Patrick Chemistry, Organic Chemistry, Pharmaceutical Chemistry, Radiation Rhenium and technetium-labeled progestins, the development of receptor-directed agents for diagnostic imaging or therapy text Chemistry Chemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.