Brain Contrasting Ability of Blood-Brain-Barrier-Permeable Nitroxyl Contrast Agents for Magnetic Resonance RedOx Imaging

The detailed in vivo contrasting abilities of nitroxyl contrast agents in mouse brain were compared using T1-weighted MRI. Five types of five-membered-ring nitroxyl radical compound, which have been used as redox responsive contrast agents in several magnetic resonance-based imaging modalities, were tested. The blood-brain-barrier (BBB)-impermeable 3-carboxy-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CxP) could not be distributed in the brain. The slightly lipophilic 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP) showed slight distribution only in the ventricle, but not in the medulla and cortex. The amphiphilic 3-methoxy-carbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MCP) had good initial uniform distribution in the brain and showed typical 2-phase signal decay profiles. A brain-seeking nitroxyl probe, acetoxymethyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl-3-carboxylate (CxP-AM), showed an accumulating phase, and then its accumulation was maintained in the medulla and ventricle regions, but not in the cortex. The lipophilic 4-(N-methyl piperidine)-2,2,5,5-tetramethylpyrroline-N-oxyl (23c) was well distributed in the cortex and medulla, but slightly in the ventricle, and showed relatively rapid linear signal decay. Nitroxyl contrast agents equipped with a suitable lipophilic substitution group could be BBB-permeable functional contrast agents. MR redox imaging, which can estimate not only the redox characteristics but also the detailed distribution of the contrast agents, is a good candidate for a theranostic tool