Improved access to linear tetrameric hydroxamic acids with potential as radiochemical ligands for zirconium(IV)-89 PET imaging

Abstract

Two new linear tetrameric hydroxamic acid ligands (3 and 4) have been prepared as potential radioligands for immunological ZrIV-89 positron emission tomography (PET) imaging. The ligands were prepared by conjugating endo-hydroxamic acid amino carboxylic acid (endo-HXA) monomers 5-[(5-aminopentyl)(hydroxy)amino]-5-oxopentanoic acid (PPH) or 2-(2-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-2-oxoethoxy)acetic acid (PPHNOCO) to trimeric desferrioxamine B (DFOB). The properties of DFOB-PPH (3) and DFOB-PPHNOCO (4) were compared with the first-inclass ligand DFO∗ (named DFOB-PBH (2) in the present work) and DFOB (1). In the initial phase of an FeIII : ZrIV competition experiment, 1 preferentially formed FeIII-1, with ZrIV-1 becoming dominant after 48 h. Tetrameric 2-4 selected ZrIV above FeIII at all times. The initial rates of formation of ZrIV-3 and ZrIV-4 were greater than ZrIV -2, which could reflect a better match between the ZrIV ionic radius and the increased volume of the coordination sphere provided by 3 and 4. In the presence of excess EDTA, ZrIV-4 dissociated more rapidly than ZrIV-2 and ZrIV-3, which indicated that any beneficial increase in water solubility conferred by the presence of ether oxygen atoms in 4 could be offset by a reduction in complex stability. Outer-sphere solvation of the ether oxygen atoms in ZrIV-4 may increase the entropic contribution to the dissociation of the complex. The rank order of the initial rate of ZrIV complexation in the presence of equimolar FeIII (highest to lowest) 4.3.2...1 together with the rate of the dissociation of the ZrIV complex (lowest to highest) 2 E 3.4 ... 1 identifies 3 as a ligand with potential value for immunological ZrIV-89 PET imaging.