CoII Complexes as Liposomal CEST Agents

Abstract

Three paramagnetic Co^II macrocyclic complexes containing 2-hydroxypropyl pendant groups, 1,1',1'',1'''-(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrayl)tetrakis- (propan-2-ol) ([Co(L1)]²⁺ , 1,1'-(4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)bis(propan-2-ol) ([Co(L2)]²⁺ ), and 1,1'-(4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)bis(octadecan-2-ol) ([Co(L3)]²⁺ ) were synthesized to prepare transition metal liposomal chemical exchange saturation transfer (lipoCEST) agents. In solution, ([Co(L1)]²⁺ ) forms two isomers as shown by ¹ H NMR spectroscopy. X-ray crystallographic studies show one isomer with 1,8-pendants in cis-configuration and a second isomer with 1,4-pendants in trans-configuration. The [Co(L2)]²⁺ complex has 1,8-pendants in a cis-configuration. Remarkably, the paramagnetic-induced shift of water ¹ H NMR resonances in the presence of the [Co(L1)]²⁺ complex is as large as that observed for one of the most effective Ln^III water proton shift agents. Incorporation of [Co(L1)]²⁺ into the liposome aqueous core, followed by dialysis against a solution of 300 mOsm L^-1 produces a CEST peak at 3.5 ppm. Incorporation of the amphiphilic [Co(L3)]²⁺ complex into the liposome bilayer produces a more highly shifted CEST peak at -13 ppm. Taken together, these data demonstrate the feasibility of preparing Co^II lipoCEST agents.

Keywords: LipoCEST; ParaCEST; amphiphilic shift reagents; water shift agents.