Synthesis of Modular Desferrioxamine Analogues and Evaluation of Zwitterionic Derivatives for Zirconium Complexation

The natural siderophore desferrioxamine B (DFOB) has been used for targeted PET imaging with ⁸⁹Zr before. However, Zr-DFOB has a limited stability and a number of derivatives have been developed with improved chelation properties for zirconium. We describe the synthesis of pseudopeptidic analogues of DFOB with azido side chains. These are termed AZA-DFO (hexadentate) and AZA-DFO* (octadentate) and are assembled via a modular synthesis from Orn-β-Ala and Lys-β-Ala. Nine different chelators have been conjugated to zwitterionic moieties by copper-catalyzed azide–alkyne cycloaddition (CuAAC). The resulting water-soluble chelators form Zr complexes under mild conditions (room temperature for 90 min). Transchelation assays with 1000-fold excess of EDTA and 300-fold excess of DFOB revealed that a short spacing of hydroxamates in (Orn-β-Ala)_3–4 leads to improved complex stability compared to a longer spacing in (Lys-β-Ala)_3–4. We found that the alignment of amide groups in the pseudopeptide backbone and the presence of zwitterionic sidechains did not compromise the stability of the Zr-complexes with our chelators. We believe that the octadentate derivative AZA-DFO* is particularly valuable for the preparation of new Zr-chelators for targeted imaging which combine tunable pharmacokinetic properties with high complex stability and fast Zr-complexation kinetics.