Organic Radical Contrast Agents for Magnetic Resonance Imaging

Rajca, Andrzej; Wang, Ying; Boska, Michael D.; Paletta, Joseph T.; Olankitwanit, Arnon; Swanson, Michael A.; Mitchell, David; Eaton, Gareth R.; Rajca, Suchada

doi:10.1021/ja3079829

Cited by 161 publications

(204 citation statements)

References 30 publications

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“…The paramagnetic effect of ROS (with unpaired electrons) has been recently reported. 28,29 The studies focusing on degenerative retina diseases show evidence that T 1 time in the retinal pigment epithelium layer was reduced in manganese-superoxidedismutase (MnSOD) knockout (KO) mice compared to healthy controls. 29 Note that MnSOD is a primary antioxidant enzyme in mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Imaging short‐lived reactive oxygen species (ROS) with endogenous contrast MRI

Tain

Scotti

et al. 2017

Magnetic Resonance Imaging

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Purpose: To characterize the relaxation properties of reactive oxygen species (ROS) for the development of endogenous ROS contrast magnetic resonance imaging (MRI). Materials and Methods: ROS-producing phantoms and animal models were imaged at 9.4T MRI to obtain T 1 and T 2 maps. Egg white samples treated with varied concentrations of hydrogen peroxide (H 2 O 2 ) were used to evaluate the effect of produced ROS in T 1 and T 2 for up to 4 hours. pH and temperature changes due to H 2 O 2 treatment in egg white were also monitored. The influences from H 2 O 2 itself and oxygen were evaluated in bovine serum albumin (BSA) solution producing no ROS. In addition, dynamic temporal changes of T 1 in H 2 O 2 -treated egg white samples were used to estimate ROS concentration over time and hence the detection sensitivity of relaxation-based endogenous ROS MRI. The relaxivity of ROS was compared with that of Gd-DTPA as a reference. Finally, the feasibility of in vivo ROS MRI with T 1 mapping acquired using an inversion recovery sequence was demonstrated with a well-established rotenone-treated mouse model (n 5 6). Results: pH and temperature changes in treated egg white samples were insignificant (<0.1 unit and <18C, respectively). T 1 relaxation time in the H 2 O 2 -treated egg white was reduced significantly (P < 0.05), while there was only small reduction in T 2 (<10%). In the H 2 O 2 -treated BSA solution that produce no ROS, there was a small change in T 1 due to H 2 O 2 itself (61%), although a significant T 2 -shortening effect was observed (>10%, P < 0.05). Also, there was a small reduction in T 1 (13 6 1%) and T 2 (1 6 2%) from molecular oxygen. The detection sensitivity of ROS MRI was estimated around 10 pM. The T 1 relaxivity of ROS was found to be much higher than that of Gd-DTPA (3.4 3 10 7 vs. 0.9 s 21 ÁmM 21 ). Finally, significantly reduced T 1 was observed in rotenone-treated mouse brain (5.1 6 2.5%, P < 0.05). Conclusion: We demonstrated in the study that endogenous ROS MRI based on the paramagnetic effect has sensitivity for in vitro and in vivo applications. Level of Evidence: 2 Technical Efficacy Stage: 2 J. MAGN. RESON. IMAGING 2018;47:222-229. R eactive oxygen species (ROS), including singlet oxygen, and hydroxyl radical (ÁOH), have long been subjects of study due to their central role in cell signaling, the aging process, and in the pathogenesis of a variety of diseases such as cardiovascular diseases, diabetes, cancer, Alzheimer's, and Parkinson's diseases. 1-5 ROS can be divided into radical species (eg, ÁOH) and nonradical species (eg, H 2 O 2 ). They are mainly produced by several different enzyme systems (eg, cytosolic enzyme) and by the mitochondrial complex I and III. 6 They can react readily with any surrounding tissue component (eg, lipids, proteins, and DNA) 2 and can initiate complicated chain processes with high biological impact (eg, Haber-Weiss or Fenton reactions). 7 The high reactivity and short lifetime of radical ROS make them very challenging to detect. For example, the lifetime...

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Section: Discussionmentioning

confidence: 99%

Imaging short‐lived reactive oxygen species (ROS) with endogenous contrast MRI

Tain

Scotti

et al. 2017

Magnetic Resonance Imaging

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“…9,10 Notable examples of this type include organic spin switching in the solid-state 11−13 and supramolecular organic radical complexes with switchable properties. 14−19 Further, while there has been interest in spin state switching in organometallic complexes, 20,21 organic molecules with switchable spin states and magnetic properties in solution remain elusive.…”

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A Noncovalently Reversible Paramagnetic Switch in Water

et al. 2013

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We report an organo-paramagnetic switch consisting of a linked bis(viologen) dication diradical that can be cycled reversibly between diamagnetic and paramagnetic states via noncovalent guest-host chemistry with cucurbit [7]uril (CB[7]) in room-temperature water. Computations suggest that the nature of the interaction between the viologen cation radical units is that of a pi dimer (pimer). Molecules with switchable magnetic properties have possible applications in spintronics, data storage devices, chemical sensors, building blocks for materials with switchable bulk magnetic properties, as well as magnetic resonance probes for biological applications. DisciplinesOrganic Chemistry | Other Chemistry | Physical Chemistry CommentsReprinted (adapted) with permission from J. Am. Chem. Soc., 2013, 135 (29) O rganic molecules with magnetic properties hold promise

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“…Synthesis Six nitroxides (6)(7)(8)(9)(10)(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][5][6][7] and Rajca's group.…”

Section: Resultsmentioning

confidence: 99%

“…[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. 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.…”

mentioning

confidence: 99%

“…[9][10][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.…”

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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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Organic Radical Contrast Agents for Magnetic Resonance Imaging

Cited by 161 publications

References 30 publications

Imaging short‐lived reactive oxygen species (ROS) with endogenous contrast MRI

Imaging short‐lived reactive oxygen species (ROS) with endogenous contrast MRI

A Noncovalently Reversible Paramagnetic Switch in Water

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

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