Technetium- and rhenium-labeled progestins: Synthesis, receptor binding and in vivo distribution of an 11β-substituted progestin labeled with technetium-99 and rhenium-186

In an effort to develop radiopharmaceuticals useful for the diagnostic imaging of steroid receptor-positive breast tumors, we have radiolabeled an analog of the antiprogestin RU486 (mifepristone), modified to incorporate an N₂S₂ chelate system in the 11β-position, with ⁹⁹Tc, ^99mTc, and ¹⁸⁶Re. For the ⁹⁹Tc-labeled analogs (3), a syn pair and two individual antidiastereomers (linker methylene versus metal-oxo; relative to the N₂S₂ plane) were isolated. In competitive radiometric binding assays, the syn pair (3syn1,2) had affinity for the progesterone receptor that was 25% that of (promegestone) R5020 (or 161% that of progesterone), and the individual anti- diastereomers had affinities of 47% (3anti1) and 7% (3anti2) that of R5020 (or 303% and 45% that of progesterone). The specific-to-nonspecific binding ratio of the ^99mTc (4) and ¹⁸⁶Re (5) 11β-linked syn systems are 75/25 and 54/46, respectively. In vivo, conjugates 4 and 5 showed progesterone receptor-mediated uptake in rat uterus, but also high uptake in non-target tissues, presumably because of the high lipophilicity of the metal complexes. Modified systems may be useful in vivo as receptor-directed agents for diagnostic imaging or treatment of steroid receptor-positive tumors.