A facile on-bead method for fully symmetric tetra-substituted DOTA derivatizations using peptoid moieties.

Abstract

The metal-chelated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has made a significant impact on the field of diagnostic imaging. This imaging mechanism is largely dependent on the four side arm functionalities around the DOTA scaffold. We previously demonstrated the effect of peptoid residue modification on these DOTA side arms, thereby conferring diverse physiochemical properties to the imaging mechanism. We generated two on-bead Eu(III)-DOTA libraries with three side arm modifications, where the remaining arm was used to attach DOTA onto the resin. However, having an on-bead fully symmetric tetra-substituted DOTA synthesis route can greatly improve the fields of diagnostic, therapeutic, and theragnostic agent development. Here, we report an efficient method for the synthesis of symmetric tetra-substituted DOTA derivatives by modification with peptoid moieties on all four arms using a conceptually unique solid-phase synthesis approach. Resins with different loading capacities were examined for synthesis feasibility and high loading resins were most effective. The reaction yields were also studied by varying the number of peptoid residues and incorporating different linkers. We have tested the binding ability of the tetra-substituted derivative with its previously tested tri-substituted analogs as model applications. Our protocol provides an efficient and facile on-bead synthesis route for fully symmetric tetra-substituted DOTA derivatizations.