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

Modular chelators: AZA-DFO and AZA-DFO* are novel hexadentate or octadentate analogues of the natural siderophore desferrioxamine bearing azidoalkyl sidechains. These chelators may be functionalized via CuAAC and are thus useful for the preparation of pharmaceutically interesting metal complexes with tailored properties. We have evaluated a series of zwitterionic derivatives for Zr complexation. In this series, a (β-Ala-Orn)₄ derivative showed the highest complex stability.

Abstract

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.

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