Nitroxides

Nitroxide stable free radicals or nitroxyl spin labels as they may be called, are chemically stable organic compounds that have an unpaired electron that results in paramagnetic properties. They generally consist of a six- member ring piperidine derivative or a five-member ring pyrroxamide derivative. The pharmacokinetics of nitroxides are similar to iodinated contrast agents and Gd- DTPA. They do not cross an intact blood brain barrier and undergo glomerular filtration as a dominant route of elimination. Their ease of conjugation to various biomolecules makes them attractive for targeting to various organ systems. Nitroxides are chemically stable and show limited in vivo metabolism. Their relaxation effects in vivo can be eliminated almost immediately by IV injection of sodium ascorbate, a strong reducing agent. This will allow an unenhanced MR study to be performed immediately after a contrast enhanced study, if the contrast study is not satisfactory alone.

The early ionic derivatives of piperidine have a 38 minute half-life and a safety ratio of between 8:1 and 100:1. Nonionic pyrrolidine derivatives are formulated with a longer half-life of 45-50 minute in dogs, estimated to be about 2 hours in humans. The LD50 in mice of this nonionic formulation is about 25 mmol/kg, making it twice as safe as earlier ionic piperidinyl preparations. Mutation and toxicity studies show no evidence of genetic or other cellular damage in mammalian cell preparations.

Larger molecular weight nitroxides exhibit increased relaxation rates as do paramagnetic ions attached to macromolecules. This phenomenon occurs when attaching five-membered nitroxide rings to fatty acids. The fatty acids attach to human serum albumin, either in vitro or in vivo, resulting in a significant increase in relaxation rate. Safety studies and clinical trials need to be performed before nitroxides will be available for use.