Nitroxides as potential contrast enhancing agents for MRI application: Influence of structure on the rate of reduction by rat hepatocytes, whole liver homogenate, subcellular fractions, and ascorbate

Abstract

With an eye toward the development of nitroxides as potential contrast enhancing agents for MRI applications, we have compared the rates of reduction of 24 nitroxides of diverse structures by rat whole liver homogenate, hepatocytes, subcellular fractions, and ascorbate (10 eq excess). Our results indicate that five-membered ring nitroxides and alpha-carboxy alpha-aryl tert-butyl nitroxides are significantly more resistant toward bioreduction than six-membered ring and heterocyclic-substituted nitroxides in all systems. In the case of six-membered ring nitroxides the presence of either negatively charged or positively charged groups increases the susceptibility toward ascorbate reduction. The presence of carboxylate groups tends to enhance the resistance of all the nitroxides toward reduction by liver homogenate, hepatocytes, and subcellular fractions. trans-Azethoxyl nitroxides exhibited the best overall resistance toward bioreduction. The T1 relaxants of selected nitroxides were measured and found to be similar.

Reversible reduction of nitroxides to hydroxylamines: Roles for ascorbate and glutathione

“…Steady-state concentrations of the ascorbate radical in the blood [41,42] may significantly exceed those for superoxide radical particularly it is increased up to 3-30 nM during vitamin C supplementation. Therefore, the observed high reactivity of the cyclic HA towards ascorbate radical may significantly contribute in the observed kinetics of both the NR reduction [11] and HA oxidation [15] measured in blood as well as in the tissues with high ascorbate content such as liver and kidney [2,18,19].…”

“…Ascorbate plays significant role in NR reduction in erythrocytes, hepatocytes and kidney cells [2,18,19], which are rich in this compound. The reduction rates of NR by ascorbate normally correlate with its electrochemical reduction potential [20] and depend on nature of the radical ring [4,[19][20][21], charge of the radical [1,19], and steric shielding of nitroxyl fragment [22][23][24]. The only product of stoichiometric reduction of the NR by ascorbate in the absence of oxygen is the hydroxylamine [1].…”

Utility Decay Rates of T1-Weighted Magnetic Resonance Imaging Contrast Based on Redox-Sensitive Paramagnetic Nitroxyl Contrast Agents

“…[1][2][3][4][5][6] The enzymatic or chemical reduction system reduces nitroxyl radicals to the corresponding hydroxylamine, [7][8][9][10][11][12] enabling us to estimate the redox status in vivo. Hypoxic conditions in the tumor, [13][14][15] biological reducing agents, 16,17) and oxidative stresses accompanying the synthesis of superoxide and/or hydroxyl radical [18][19][20] can enhance the reduction of nitroxyl radicals in vivo.…”

“…22,23) Since the T 1 relaxation of protons can be affected by paramagnetic nitroxyl electron spin, changing the MRI contrast before and after administration of the nitroxyl contrast agent can reflect the amount of nitroxyl contrast agent in addition to providing simultaneous anatomical mapping, similar to Gd 3ϩ . Despite a number of pharmacokinetic studies, 7,24,25) rapid in vivo reduction of the nitroxyl contrast agent was not as useful as an MRI contrast agent in early 1980s. 26) At that time, relatively low T 1 relaxivity of nitroxyl contrast agents was another problem for obtaining clinically and/or experimentally utilizable T 1 -contrast enhancement.…”

Synthesis of Novel Nitroxide Radical Polymer Materials for Imaging and Energy Storage Applications

“…315,316 To counteract this quick deactivation and low relaxivity, nitroxides have to be employed in higher concentrations. There are several possible ways to address these issues.…”