Analysis of paraCEST and water interactions of Fe(II) and Co(II) macrocyclic complexes for MRI contrast.
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Paramagnetic Co(II) and Fe(II) macrocyclic complexes were prepared with the goal of developing paraCEST MRI imaging agents as well as introducing a bound water ligand to produce paramagnetically shifted water 1H resonances. Three 12-membered macrocycles with pendent amide groups including 1,7-bis(carbamoylmethyl)-1,4,7,10-tetraazacyclodocane (DCMC), 4,7,10-tris(carbamoylmethyl)-,4,7,10-triaza-12- crown-ether (N3OA), and 4,10-bis(carbamoylmethyl)-4,10-diaza12-crown-ether (NODA) were prepared and their Co(II) complexes were characterized in the solid state and in solution. CEST peaks ranging from 60 ppm to 70 ppm, attributed to NH groups of the pendent amides, were identified. Variable-temperature 17O NMR spectra of Co(II) and Fe(II) NODA complexes were consistent with rapid exchange of the water ligand with bulk water. Notably, the Co(II) and Fe(II) complexes presented here produced substantial paramagnetic shifts of bulk water 1H resonances, independent of having an inner-sphere water. Another macrocyclic complex of the 1,4,8,11-tetrakis(carbamoylmethyl)-1,4,8,11 tetraazacyclotetradecane (CCRM) ligand with Co(II) is a paraCEST agent that produces four distinct CEST peaks, all with strong intensity (20-32 % CEST), and with the furthest shifted CEST peak at an impressive 112 ppm at 37 ⁰C and pH 7.3-7.5. Notably, more than one conformation may be produced as it is shown that that this Co(II) complex isomerizes upon being heated, and permanently retains a new structure, producing two very intense CEST peaks (35% CEST) at 124 and 45ppm. The Z-spectra recorded on the new complex by NMR and MRI studies show that the complex has strong potential as a paraCEST MRI contrast agent. Both isomers were studied in biological media to access their properties towards in vivo imaging.