Pharmacokinetics and metabolic fate of two nitroxides potentially useful as contrast agents for magnetic resonance imaging.

Paramagnetic nitroxyl-containing compounds have been useful as contrast agents in magnetic resonance imaging (MRI) experiments in animals. Preliminary information on the metabolic fate, pharmacokinetic behavior, stability in tissues, and chemical reduction of two prototypic nitroxides, PCA and TES, is presented. In the dog TES was eliminated more rapidly than PCA. More than 80 % of the dose of both nitroxides was recovered in urine within 6 hours. Nitroxides were reduced in vivo to their corresponding hydroxylamines. No other metabolite was observed. Measured reducing activity in tissue homogenates was greater in liver or kidney than in brain, lung or heart. In each tissue PCA was more stable than TES. PCA was also more resistant to reduction by ascorbic acid at physiologic pH. These preliminary results favor the use of PCA, a pyrrolidinyl nitroxide, over TES, a piperidinyl nitroxide, for MRI contrast enhancement.

Brain nuclear magnetic resonance imaging enhanced by a paramagnetic nitroxide contrast agent: preliminary report.

Contrast-enhancing agents for demonstrating abnormalities of the blood-brain barrier may extend the diagnostic utility of proton nuclear magnetic resonance (NMR) imaging. "TES," a nitroxide stable free radical derivative, was tested as a central nervous system contrast enhancer in dogs with experimentally induced unilateral cerebritis or radiation cerebral damage. After intravenous injection of TES, the normal brain showed no change in NMR appearance, but areas of disease demonstrated a dramatic increase (up to 45%) in spin-echo intensity and a decrease in T1 relaxation times. The areas of disease defined by TES enhancement were either not evident on the nonenhanced NMR images or were better defined after contrast administration. In-depth tests of toxicity, stability, and metabolism of this promising NMR contrast agent are now in progress.

Work in progress: nuclear magnetic resonance study of a paramagnetic nitroxide contrast agent for enhancement of renal structures in experimental animals.

A piperidinyl nitroxide stable free radical derivative, TES, was tested as an NMR contrast enhancer of renal structures in normal animals and animals with experimentally induced unilateral renal ischemia, renal vascular congestion, and hydronephrosis. Physiologic measurements indicated that TES is rapidly excreted in the urine with a clearance rate equal to the glomerular filtration rate. Because the compound is strongly paramagnetic, it increases the observable NMR intensity within the kidneys and urine in relatively low doses (0.04 to 0.9 g/kg). TES-enhanced spin echo renal images clearly demonstrated the presence of disease and functional abnormalities in diseased kidneys. These abnormalities were either not evident or only indirectly suggested on nonenhanced NMR images.