Synthesis of Short and Versatile Heterobifunctional Linkers for Conjugation Purposes of Bioactive Molecules with (Radio-)Labels

The preparation of a series of short and versatile (eleven and twelve atom length) hydrophilic heterobifunctional linkers from low-cost chemicals using simple experimental setups is described.
The approach can be used to connect high molecular weight bioactive molecules with azamacrocycles to enable radiolabeling with radiometals. The ring opening reaction of three cyclic anhydrides with 2-(2-aminoethoxy)ethanol afforded precursors 4a–c, which were subsequently converted into various heterobifunctional linkers for radiofluorination, Huisgen–Click approaches, or Staudinger ligation and for solid-phase peptide synthesis. As examples for successful building block ligation using the strain-promoted Huisgen cycloaddition on the one hand and the traceless Staudinger approach on the other hand, the Cetuximab antibody was modified by using 13a in a convenient two-step procedure.