Synthesis, characterization and screening of Re(I)/Tc(I)-aryl carborane derivatives capable of targeting the estrogen receptor

1845 Objectives: The objective of this study was to synthesize a series of organometallic compounds derived from carboranes and to evaluate their ability to bind to the estrogen receptor (ER). Of particular focus was the preparation and screening of Re(I) and Tc(I) aryl-carborane derivatives as organometallic mimics of estradiol. Methods: A series of six dicarbo-closo-dodecaboranes containing one or more functionalized aryl groups were prepared and reacted with [Re(CO)3(H2O)3]Br. To improve the yields of the rhenacarboranes, a novel synthetic procedure was developed which involved performing reactions in aqueous fluoride solutions heated by microwave radiation. Notably, this methodology was extended to produce 99mTc and 188Re labeled analogues. The non-radioactive Re-carborane complexes and the corresponding closo-carboranes were subsequently evaluated for ER binding using a standard 3H-estradiol competitive binding assay. Results: A novel synthetic methodology for the preparation of metallocarboranes was developed that significantly improves overall yield and decreases reaction times. Conventional methods used to prepare Re-carborane reactions require extended heating times and often produce complexes in low yield particularly for sterically hindered systems. Microwave heated reactions, in contrast, were complete in under 30 minutes affording the desired products in high yield (>70%). This methodology has been successfully extended to generate 99mTc and 188Re-carborane analogues. The ER receptor binding assays revealed carborane derivatives that possess Ki values below 20 nM. Conclusions: A series of Re(I)-metallocarboranes were prepared in a single step from [Re(CO)3(H2O)3]Br using microwave heating. From a small library of compounds, closo-carborane derivatives and the corresponding rhenium analogues were identified that exhibit potent ER-binding affinities. Details of the new synthetic procedure, including work involving 99mTc and 188Re, along with the results of the biological screening studies will be presented.