Asymmetrical Nitrido Tc-99m Heterocomplexes as Potential Imaging Agents for Benzodiazepine Receptors

Abstract

The design, synthesis, and biological evaluation of nitrido technetium-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 [(99m)Tc(N)(PXP)](2+) (PXP = diphosphine ligand) as molecular building-blocks for assembling the structure of the final radiopharmaceuticals through the application of the so-called 'bifunctional' and 'integrated' approaches. This required the synthesis of the ligands H(2)BZ1, H(2)C1, and H(2)C2 (Figures 1 and 2) derived from desmethyldiazepam. In turn, these ligands were reacted with [(99m)Tc(N)(PXP)](2+) to afford the complexes [(99m)Tc(N)(PXP)(L)] (L = BZ1, C1, C2). 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 characterized by spectroscopic and analytical methods. Results showed that the complexes [(99m)Tc(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[triple bond]N core. With the ligand H(2)BZ1, two isomers were obtained depending on the syn or anti orientation of the pendant benzodiazepine group relative to the Tc[triple bond]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 rat's cerebral membranes using the corresponding Tc-99g complexes.

Mapping neuroreceptors with metal-labeled radiopharmaceuticals

“…IC 50 > 1 μM was obtained for the analogs. 49 Amyloids. Though amyloids do not qualify as neuroreceptors, imaging amyloids require the ligand to cross the BBB.…”

The role of coordination chemistry in the development of target-specific radiopharmaceuticals

“…The [ 99m TcMN] 21 core has also been used for 99m Tc-labeling of small peptides and the benzodiazepine receptor ligands. [53][54][55] The PXP bisphosphine ligands (Fig. 9: X ~O and NR) are used as coligands to stabilize the [ 99m TcMN] 21 core, and the bifunctional chelators containing thiolate-S, amine-N or carboxylate-O donors are attached to the peptide or benzodiazepine receptor ligands.…”

Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides

“…The [Tc≡N] 2+ core forms Tc(V)-nitrido complexes with various chelators[120][121][122][123][124][125][126]. The [ 99m Tc≡N] 2+ core has been used for 99m Tc-labeling of small peptides and benzodiazepine receptor ligands[127][128][129]. The PXP bisphosphine ligands(Figure 7)are used as coligands to stabilize the [ 99m Tc≡N] 2+ core, and the BFCs containing thiolate-S, amine-N or carboxylate-O donors are attached to the peptide or benzodiazepine receptor ligands.…”