Evaluation of nonionic nitroxyl lipids as potential organ-specific contrast agents for magnetic resonance imaging

Considering their intrinsic properties of accumulation in the hepatic tissue, we have synthesized nitroxyl-containing lipids as potential organ-specific contrast agents for magnetic resonance imaging (MRI). Their resistance to reduction by ascorbate and in liver homogenates, and their relaxivity in different media were investigated and compared to those of free carboxyl-Proxyl (3-carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl) and Tempamaine (4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl). With respect to the reduction rates by ascorbate, the lipid derivatives show the same well-known order of reactivity as carboxy-Proxyl and Tempamine, the five-membered nitroxyls being more stable than the six-membered compounds. However the binding of the piperidinoxyl compounds to the fatty acids confers to those lipid derivatives a markedly increased stability. Similarly, in liver homogenates, the nitroxyl lipids remained unchanged more than 20 min, contrarily to carboxy-Proxyl and Tempamine. The measurements of spin-lattice relaxation time (T1) in biological media have demonstrated a higher relaxivity of nitroxyl lipids, which can be related to their interaction with proteins. Tested in vivo, one of the synthesized compounds (0.75 mmol/kg) produced an enhancement of 44 +/- 12% of the hepatic signal 5 min after intraportal injection in T1-weighted images. The potential applicability of the other nitroxyl lipids as contrast agents for MRI was limited in the in vivo studies by an unexpected toxicity. Work is currently in progress to improve the therapeutic index of the present class of nitroxyl lipids.