Design and characterization of a new irreversible responsive PARACEST MRI contrast agent that detects nitric oxide

Irreversible responsive PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) MRI contrast agents constitute a new type of agent for molecular imaging. To investigate the utility of this approach, a novel PARACEST MRI contrast agent, Yb(III)-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid)-orthoaminoanilide (Yb-DO3A-oAA), was developed that detects nitric oxide (NO). The agent exhibited two CEST effects at -11 ppm and +8 ppm, which were assigned to chemical exchange from amide and amine functional groups, respectively. The effects of pH, temperature, and concentration were investigated to characterize the complex and to optimize PARACEST detection. This responsive PARACEST MRI contrast agent incurred an irreversible covalent change in the presence of NO and 02, which caused an irreversible disappearance of both PARACEST effects from MR images. The NO-dependent response of a relaxivity-based MRI contrast agent, Gd-DO3A-oAA, was investigated for comparison. This report highlights the advantages of irreversible MRI contrast agents, demonstrates that large changes in PARACEST can be used to create a highly responsive agent, and indicates challenges that must be overcome to apply this type of contrast agent to in vivo biomedical applications in molecular imaging.