Asymmetrycal Nitrido Tc-99m Heterocomplexes as Potential Imaging Agents of Benzodiazepine Receptors

The design, syntheses and biological evaluation of nitrido-Tc-99m complexes for imaging benzodiazepine receptors are described. The design was performed by selecting the precursor biologically active substrate desmethyldiazepam, and the reactive metal-containing fragment [99mTc(N)(PXP)]2+ as molecular building-blocks for assembling the structure of the final radiopharmaceuticals through tha application of the so-called bifunctional and integrated approaches. This required the synthesis of some ligands derived from desmethyldiazepam. In turn, these ligands were reacted with [99mTc(N)(PXP)]2+ to afford the complexes [99mTc(N)(PXP)(L)]. The chemical nature of the resulting Tc-99m radiopharmaceuticals was investigated using chromatographic methods and by comparison with the analogous complexes prepared with the long-lived isotope Tc-99g and characterised by spectroscopic and analytical methods. results showed that the complexes [99mTc(N)(PXP)(L)] are neutral and possess an asymmetrical five-coordinated structure in which two different bidentate ligands, PXP and L, are coordinated to the same Tc(N) core. With the ligand H2Bz1 two isomers were obtained, depending on the syn or anti orientation of the pendant benzodiazepine group relative to the Tc(N) multiple bond. Biodistribution studies of Tc-99m complexes were carried out in rats, and affinity for benzodiazepine receptors was assessed through in vitro binding experiments on isolated rats cerebral membranes using the corresponding Tc-99g complexes