Efficient Synthesis of 1,4,7-Triazacyclononane and 1,4,7-Triazacyclononane-Based Bifunctional Chelators for Bioconjugation

The reaction of diethylenetriamine with chloroacetaldehyde yielded a bicyclic aminal intermediate for the synthesis of 1,4,7-triazacyclononane (TACN), a macrocyclic polyamine the derivatives of which find applications as catalysts, bleaching agents, and chelators for medical imaging. This new synthetic protocol outperforms the synthetic methods described so far because it does not involve any cyclization step. Moreover, this aminal intermediate allowed access to a new family of TACN derivatives functionalized on the carbon skeleton, for example, C-aminomethyl-TACN. This novel compound is a precursor of valuable bifunctional chelating agents for nuclear medicine, in particular, for the preparation of PET imaging agents after bioconjugation and metallation with Ga-68 or Cu-64.