Co(II) 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 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 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.