Synthesis of nitroimidazole substituted 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioximes (propylene amine oximes, PnAOs): Ligands for technetium-99m complexes with potential for imaging hypoxic tissue

A series of 2-substituted-1,3-diaminopropanes ( 1b-1f, 1h ) have been synthesized as precursors to nitroimidazole-substituted 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime ( 21b, 21d, 21e and 26a-26c ) (Propylene Amine Oxime, PnAO) ligands. 3-Chloro-3-methyl-1-(2- or 4-nitro-I H -imidazol-1-yl)-2-nitroso-butanes ( 18a-e ) required for the syntheses of nitroimidazole substituted propylene amine oxime (PnAO) ligands were prepared from the corresponding dimethylallyl-nitroimidazoles ( 17a-17e ) by the addition of nitrosyl chloride. A number of nitroimidazole derivatized PnAO ligands possessing potential for either electrostatic, hydrophobic, or hydrophilic interactions were synthesized as precursors to technetium-99m complexes under investigation as potential imaging agents of hypoxia. Derivatives of PnAO, substituted at carbon one, were prepared using the 3-chloro-3-methyl-1-(2- or 4-nitro-1 H -imidazol-1-yl)-2-nitrosobutanes. Three PnAOs 26a-26c derivatized at the central carbon atom, were prepared using 3-bromo-3-methylbutane-2-one ( 24 ).