Novel ascorbic acid-resistive nitroxide in a lipid emulsion: An efficient brain imaging contrast agent for MRI of small rodents

Emoto, Miho C.; Yamada, Ken Ichi; Yamato, Masayuki; Fujii, Hirotada

doi:10.1016/j.neulet.2013.04.044

Cited by 22 publications

(24 citation statements)

References 18 publications

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“…In 1 H-NMR spectroscopy the assignment was achieved as a hydroxylamine by adding excess of hydrazobenzene. EPR spectra of ibuprofen-nitroxides 3-5 in dimethyl sulfoxide (DMSO) show triplet patterns due to 14 N hyperfine splitting, a N =1.43-1.53 mT, and g-values of about 2.006, similar to those for tetramethyl-linked 1 and 2 (Figs. S6-S11).…”

Section: H-nmr and Epr Spectra Of 1-6mentioning

confidence: 77%

“…They had different reduction rates for reductants such as ascorbic acid (AsA), and these were applied as an invivo probe. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] The rate constant of reduction of a nitroxide probe in vitro is expected to be a guideline of its half-life in vivo. [9][10][11] The rate constants of them are greatly different and could not measure under the same conditions.…”

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confidence: 99%

“…TEMPO radical is highly sensitive for reductants and a good detection reagent for AsA, 5,11) but, its half-life as an in-vivo probe was too short and unusable. 14) It has been shown that ibuprofen-PROXYL passed through the blood-brain barrier (BBB) in mice and was indicated the anti-inflammatory action in inflamed mice brains. Real-time changes in the redox status of mice brains were successfully visualized by magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) imaging.…”

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confidence: 99%

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Synthesis and Reduction Kinetics of Five Ibuprofen–Nitroxides for Ascorbic Acid and Methyl Radicals

et al. 2016

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).Key words Ibuprofen-nitroxide; reduction kinetics; ascorbic acid; methyl radical; Fenton reaction; electron paramagnetic resonance intensityThe representative nitroxide radicals, a six-memberedring nitroxide, tetramethylpiperidine-1-oxyl (TEMPO), and a five-membered-ring nitroxide, tetramethylpyrrolidine-1-oxyl (PROXYL), have been used as in-vivo probes. Recently, various nitroxides in which the tetramethyl groups around the nitroxyl group were replaced by bulkier groups have been synthesized. They had different reduction rates for reductants such as ascorbic acid (AsA), and these were applied as an invivo probe. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] The rate constant of reduction of a nitroxide probe in vitro is expected to be a guideline of its half-life in vivo.9-11) The rate constants of them are greatly different and could not measure under the same conditions. 9,10,17) For the nitroxides resistant to AsA, we planned to examine the measurement of their rate constants using methyl radicals formed by Fenton reaction. The balance between their sensitivity for reductants and half-life is important for use of nitroxide as an in-vivo probe. TEMPO radical is highly sensitive for reductants and a good detection reagent for AsA, 5,11) but, its half-life as an in-vivo probe was too short and unusable. 14) It has been shown that ibuprofen-PROXYL passed through the blood-brain barrier (BBB) in mice and was indicated the anti-inflammatory action in inflamed mice brains. Real-time changes in the redox status of mice brains were successfully visualized by magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) imaging. Both shows a functionality as a theranostic compound.18) However, for exploring the redox status of brain, nitroxides with different reduction rate for reductants such as reactive oxygen species (ROS) or vitamin C or E are required. Five nitroxides with different reduction activities and their condensates with ibuprofen were synthesized (Fig. 1). The reduction reactivity of the five ibuprofen-nitroxides were measured by addition of AsA, and for the reduction-resistant nitroxides by the addition of the methyl radicals produced by the Fenton reaction. The reduction rate constants of the five ibuprofen-nitroxides for AsA or methyl radicals were determined and compared with the suitable time-dependent reduction-decay curve. Results and DiscussionSynthesis Six nitroxides (6-11) were synthesized by the synthetic methods shown in Chart S1. Sterically shielded nitroxides 7, 10 and 11 were synthesized according to the method established by Yamada's group 4-7) and Rajca's group. [9][10][11] Since there were some low-yield reaction steps in the synthesis of the sterically shielded nitroxides (7, 10, 11), the reaction conditions were partially improved and synthesis was achieved.Nitroxides with tetramethyl groups 6, 8 and 9 were synthesized by conventional methods. [19][20][21]

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Section: H-nmr and Epr Spectra Of 1-6mentioning

confidence: 77%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Synthesis and Reduction Kinetics of Five Ibuprofen–Nitroxides for Ascorbic Acid and Methyl Radicals

et al. 2016

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“…To consider the possibility of intracellular contrast, it may be advantageous to design spin-labeled agents that are resistant to chemical reduction. In a relevant development, Emoto et al [39] described an ascorbic acid resistant, cell permeable nitroxide with a long half-life in mouse brain (determined by contrast in T 1 -weighted MRI). This nitroxide contains tetraethyl substitutions in place of the typical tetramethyl ring substitutions, which shield the N–O moiety from reacting with intracellular reductants.…”

Section: Discussionmentioning

confidence: 99%

A Metal-Free Method for Producing MRI Contrast at Amyloid-β

Hilt

Tang

Walton

et al. 2016

JAD

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Alzheimer’s disease (AD) is characterized by depositions of the amyloid-β (Aβ) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aβ in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aβ has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aβ. The molecule is comprised of a fluorene (a molecule with high affinity for Aβ) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of SLF into live mice resulted in good brain penetration, with the compound able to generate contrast 24-hr post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by magnetic resonance imaging (MRI).

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“…7,8) We previously investigated the pharmacokinetics of nitroxyl radicals, paramagnetic probes sensitive to biological redox, in mice using compact MRI with 1.5 T permanent magnets.…”

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Application of a Compact Magnetic Resonance Imaging System with 1.5 T Permanent Magnets to Visualize Release from and the Disintegration of Capsule Formulations <i>in Vitro</i> and <i>in Vivo</i>

Takeshita

Okazaki

Shinada

et al. 2017

Biological & Pharmaceutical Bulletin

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Although magnetic resonance imaging (MRI) has potential in assessments of formulations, few studies have been conducted because of the size and expense of the instrument. In the present study, the processes of in vitro and in vivo release in a gelatin capsule formulation model were visualized using a compact MRI system with 1.5 T permanent magnets, which is more convenient than the superconducting MRI systems typically used for clinical and experimental purposes. A Gd-chelate of diethylenetriamine-N,N,N′,N″,N″-pentaacetic acid, a contrast agent that markedly enhances proton signals via close contact with water, was incorporated into capsule formulations as a marker compound. In vitro experiments could clearly demonstrate the preparation-dependent differences in the release/disintegration of the formulations. In some preparations, the penetration of water into the formulation and generation of bubbles in the capsule were also observed prior to the disintegration of the formulation. When capsule formulations were orally administered to rats, the release of the marker into the stomach and its transit to the duodenum were visualized. These results strongly indicate that the compact MRI system is a powerful tool for pharmaceutical studies.Key words magnetic resonance imaging (MRI); capsule formulation; release; disintegration; gadoliniumchelate of diethylenetriamine-N,N,N′,N″,N″-pentaacetic acid (Gd-DTPA) Capsule formulations are convenient drug delivery systems that control the stability and release of drugs in the gastrointestinal tract; therefore, they are used in a wide range of drugs that are administered orally. The performance of formulations is influenced by the swelling and/or disintegration of capsules, the penetration of water in formulations, and the release of drug contents in the gastrointestinal tract. Since these processes influence the bioavailability of drugs, visualizing these processes may provide direct information for assessing capsule formulations.Magnetic resonance imaging (MRI) is a non-invasive imaging technique that provides unique information that is useful for diagnostic purposes. MRI is sensitive to the local concentrations and physical state of protons, mainly those in water in biological specimens. The advantages of MRI over other non-invasive imaging techniques such as γ-scintigraphy are its high spatial and temporal resolutions and representation of anatomical structures. Paramagnetic compounds such as chelate compounds of Gd(III) are typically used as contrast agents.1) Gd-chelates shorten the longitudinal relaxation time (T 1 ) of protons in water by making close contact with water, which markedly enhances proton signals on T 1 -weighted magnetic resonance (MR) images. In contrast, the dry form of Gd-chelates provides no signal on MR images without contact with water.2,3) The release of substances from tablets and capsules has been visualized in rats 3,4) and humans 2) using this technique. Despite its usefulness, few studies have employed MRI in pharmaceutical analyses because of ...

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Novel ascorbic acid-resistive nitroxide in a lipid emulsion: An efficient brain imaging contrast agent for MRI of small rodents

Cited by 22 publications

References 18 publications

Synthesis and Reduction Kinetics of Five Ibuprofen–Nitroxides for Ascorbic Acid and Methyl Radicals

Synthesis and Reduction Kinetics of Five Ibuprofen–Nitroxides for Ascorbic Acid and Methyl Radicals

A Metal-Free Method for Producing MRI Contrast at Amyloid-β

Application of a Compact Magnetic Resonance Imaging System with 1.5 T Permanent Magnets to Visualize Release from and the Disintegration of Capsule Formulations <i>in Vitro</i> and <i>in Vivo</i>

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