CoII Complexes as Liposomal CEST Agents

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 ¹H 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 ¹H 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.