Mixed Liquid and Solid Phase Synthesis of Isopeptidic Desferrioxamine Analogues for Complexation of Zirconium

⁸⁹Zr has a number of advantageous properties for PET-imaging, but optimal chelators for its widespread clinical application still need to be found. Tetrahydroxamates derived from the natural siderophore DFOB are promising candidates in this context. This study describes a solid-phase approach to isopeptide analogs of DFOB (termed ipDFO*) with four hydroxamate groups for stable Zr(IV)-chelation. The route uses either commercial or easily available Fmoc-protected precursors and allows the synthesis of ipDFO* and clickable AZA−ipDFO* derivatives in only a few hours. The solid-phase synthesis reduces the workload for the synthesis of ipDFO* and AZA−ipDFO* derivatives thus significantly compared to a previous multistep solution synthesis. The route is also modular and allows the synthesis of various ipDFO* derivatives with variation in the spacer length between the hydroxamate groups. This spacing is a critical parameter for finding the optimal chelator for hard metal cations like Zr(IV). It might thus help to speed up the search for an ideal Zr-chelator for PET-imaging and might also allow the extension to other metal cations of different size.