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Nitroxide compounds have been used as redox-sensitive imaging probes by electron paramagnetic resonance (EPR) for assessing oxidative stress in vivo. Fast redox reactions of nitroxide radicals are favorable for assessment of higher redox sensitivity; however, a variety of nitroxides have not been trialed for use as imaging probes due to their very rapid in vivo reduction, which cannot be captured at the slow operation speed of existing EPR imagers. To overcome this limitation, we improved our EPR system to provide a stable and highly sensitive imaging operation. We challenged the improved EPR imager to perform three-dimensional (3D) EPR imaging of mouse brain using two useful nitroxide imaging probes, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol) and 2,6-dispiro-4',4"-dipyrane-piperidine-4-one-N-oxyl (DiPy). The second-order rate constant of DiPy with ascorbic acid is 10 times larger than that of Tempol. The improved EPR imager obtained clear 3D EPR images of mouse brain and demonstrated that Tempol could exist with an unpaired electron. The imager also successfully obtained 3D EPR images of mouse head after administration of DiPy. As 126 projections can be acquired in a period of 6 s, 3D EPR imaging can visualize the sequential process of DiPy entering the brain, being distributed within the brain, and being reduced within the brain. These improvements to the EPR imager will enable useful nitroxide imaging probes that were previously unsuitable as imaging probes due to their rapid reduction to be considered for use for sensitive redox assessment in an in vivo system.

The multi-modal imaging contrast agent has been attracted an increased interest to the tumor detecting and diagnosis in these recent years since the multi-modal imaging technology combines the adva...

The imaging of the biodistribution and pharmacokinetics is critical in understanding the complexity of drug delivery mechanisms, the status of the disease, and the monitoring of the treatment progr...

X-band (9.4 GHz) electron paramagnetic resonance (EPR) and electron paramagnetic resonance imaging (EPRI) were used for elucidating structural aspects of the stratum corneum (SC). We found that psoriasis vulgaris (PV)-SC has a less-ordered structure than that of the control SC, indicating the abnormal architecture of PV-SC. Different spectra were observed for the PV-SC. The three-line spectral pattern suggests that the 5-doxylstearic acid (5-DSA) is mobile or less rigid in the SC. The simulated order parameter (S0) value obtained for 5-DSA in the SC was approximately 0.20. The statistical analysis suggests that the value of the PV-SC is significantly smaller than that of the control (p < 0.01). Thus, we suggest that this EPR assay is of great use for evaluating SC function. In addition, the EPRI of various SC samples provides a useful image concerning SC status. A strong red image was observed for the PV skin. No red lesion region was observed in the control. The EPR images differentiated various sizes and number distribution concerning the disordered states in the SC.

Radiation treatment success and high tumor oxygenation and success have been known to be highly correlated. This suggests that radiation therapy guided by images of tumor regions with low oxygenation, oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. Before applying the technique to human subjects, OGRT needs to be tested in animals, most easily in rodents. Electron paramagnetic resonance imaging provides quantitative maps of tissue and tumor oxygen in rodents with 1 mm spatial resolution and 1 torr pO2 resolution at low oxygen levels. The difficulty of using mouse models is their small size and that of their tumors. To overcome this we used XRAD225Cx micro-CT/ therapy system and 3D printed conformal blocks. Radiation is delivered first to a uniform 15% tumor control dose for the whole tumor and then a boost dose to either hypoxic tumor regions or equal volumes of well oxygenated tumor. Delivery of the booster dose used a multiple beam angles to deliver radiation beams whose shape conforms to that of all hypoxic regions or fully avoids those regions. To treat/avoid all hypoxic regions we used individual radiation blocks 3D-printed from acrylonitrile butadiene styrene polymer infused with tungsten particles fabricated immediately after imaging to determine regions with pO2 less than 10 torr. Preliminary results demonstrate the efficacy of the radiation treatment with hypoxic boosts with syngeneic FSa fibrosarcoma tumors in the legs of C3H mice.

In this part we shall outline the challenges one faces while developing time-domain radiofrequency (RF) EPR imaging spectrometer for in vivo studies. Time-domain or FT-EPR is quite a different animal compared to the CW modality. The evolution of FT-EPR instrumentation at the National Cancer Institute, NIH, USA and representative examples of application in cancer research are outlined in this article.

A thorough investigation of biomimetic polydopamine (PDA) by Electron Paramagnetic Resonance (EPR) is shown. In addition, temperature dependent spectroscopic EPR data are presented in the range 3.8-300 K. Small discrepancies in magnetic susceptibility behavior are observed between previously reported melanin samples. These variations were attributed to thermally acitivated processes. More importantly, EPR spatial-spatial 2D imaging of polydopamine radicals on a phantom is presented for the first time. In consequence, a new possible application of polydopamine as EPR imagining marker is addressed.

This article describes an improved method for suppressing image artifacts in the visualization of 14 N- and 15 N-labeled nitroxyl radicals in a single image scan using electron paramagnetic resonance (EPR). The purpose of this work was to solve the problem of asymmetric EPR absorption spectra in spectral processing. A hybrid function of Gaussian and Lorentzian lineshapes was used to perform spectral line-fitting to successfully separate the two kinds of nitroxyl radicals. This approach can process the asymmetric EPR absorption spectra of the nitroxyl radicals being measured, and can suppress image artifacts due to spectral asymmetry. With this improved visualization method and a 750-MHz continuous-wave EPR imager, a temporal change in the distributions of a two-phase paraffin oil and water/glycerin solution system was visualized using lipophilic and hydrophilic nitroxyl radicals, i.e., 2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinyloxy (16-DOXYL stearic acid) and 4-hydroxyl-2,2,6,6-tetramethylpiperidine-d 17 -1- 15 N-1-oxyl (TEMPOL-d 17 - 15 N). The results of the two-phase separation experiment verified that reasonable artifact suppression could be achieved by the present method that deals with asymmetric absorption spectra in the EPR imaging of 14 N- and 15 N-labeled nitroxyl radicals.

Purpose Electron paramagnetic resonance imaging has surfaced as a promising noninvasive imaging modality that is capable of imaging tissue oxygenation. Due to extremely short spin-spin relaxation times, electron paramagnetic resonance imaging benefits from single-point imaging and inherently suffers from limited spatial and temporal resolution, preventing localization of small hypoxic tissues and differentiation of hypoxia dynamics, making accelerated imaging a crucial issue. Methods In this study, methods for accelerated single-point imaging were developed by combining a bilateral k-space extrapolation technique with model-based reconstruction that benefits from dense sampling in the parameter domain (measurement of the T2* decay of a free induction delay). In bilateral kspace extrapolation, more k-space samples are obtained in a sparsely sampled region by bilaterally extrapolating data from temporally neighboring k-spaces. To improve the accuracy of T2* estimation, a principal component analysis-based method was implemented. Results In a computer simulation and a phantom experiment, the proposed methods showed its capability for reliable T2* estimation with high acceleration (8-fold, 15-fold, and 30-fold accelerations for 61×61×61, 95×95×95, and 127×127×127 matrix, respectively). Conclusion By applying bilateral k-space extrapolation and model-based reconstruction, improved scan times with higher spatial resolution can be achieved in the current single-point electron paramagnetic resonance imaging modality. Magn Reson Med 73:1692–1701, 2015. © 2014 Wiley Periodicals, Inc.

PURPOSE: The purpose of this study was to develop an X-Band electron paramagnetic resonance imaging protocol for visualization of oxidative stress in biopsies.METHODS: The developed electron parama ...

A scalable synthetic route for 15N-labeled 4-oxo-2,2,6,6-tetraethylpiperidine nitroxide (15N-TEEPONE) is described. This 15N-labeled nitroxide is suitable for electron paramagnetic resonance imaging of brain, and its higher sensitivity compared with that of its 14N-counterpart is an important advantage of the labeled derivative.

In this part we shall outline the challenges one faces while developing time-domain radiofrequency (RF) EPR imaging spectrometer for in vivo studies. Time-domain or FT-EPR is quite a different animal compared to the CW modality. The evolution of FT-EPR instrumentation at the National Cancer Institute, NIH, USA and representative examples of application in cancer research are outlined in this article.

Purpose EPR spectroscopy promises quantitative images of important physiologic markers of animal tumors and normal tissues, such as pO2, pH, and thiol redox status. These parameters of tissue function are conveniently reported by tailored nitroxides. For defining tumor physiology, it is vital that nitroxides are selectively localized in tumors relative to normal tissue. Furthermore, these paramagnetic species should be specifically taken up by cells of the tumor, thereby reporting on both the site of tumor formation and the physiological status of the tissue. This study investigates the tumor localization of the novel nitroxide, cis-3,4-di(acetoxymethoxycarbonyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl 3 relative to the corresponding di-acid 4.

Electron paramagnetic resonance imaging (EPRI) has been used to noninvasively provide 3D images of absolute oxygen concentration (pO2) in small animals. These oxygen images are well resolved both spatially (~1 mm) and in pO2 (1-3 mmHg). EPRI preclinical images of pO2 have demonstrated extremely promising results for various applications investigating oxygen related physiologic and biologic processes as well as the dependence of various disease states on pO2, such as the role of hypoxia in cancer. Recent developments have been made that help to progress EPRI towards the eventual goal of human application. For example, a bimodal crossed-wire surface coil has been developed. Very preliminary tests demonstrated a 20 dB isolation between transmit and receive for this coil, with an anticipated additional 20 dB achievable. This could potentially be used to image local pO2 in human subjects with superficial tumors with EPRI. Local excitation and detection will reduce the specific absorption rate limitations on images and eliminate any possible power deposition concerns. Additionally, a large 9 mT EPRI magnet has been constructed which can fit and provide static main and gradient fields for imaging local anatomy in an entire human. One potential obstacle that must be overcome in order to use EPRI to image humans is the approved use of the requisite EPRI spin probe imaging agent (trityl). While nontoxic, EPRI trityl spin probes have been injected intravenously when imaging small animals, and require relatively high total body injection doses that would not be suitable for human imaging applications. Work has been done demonstrating the alternative use of intratumoral (IT) injections, which can reduce the amount of trityl required for imaging by a factor of 2000- relative to a whole body intravenous injection. The development of a large magnet that can accommodate human subjects, the design of a surface coil for imaging of superficial pO2, and the reduction of required spin probe using IT injections all are crucial steps towards the eventual use of EPRI to image pO2 in human subjects. In the future this can help investigate the oxygenation status of superficial tumors (e.g., breast tumors). The ability to image pO2 in humans has many other potential applications to diseases such as peripheral vascular disease, heart disease, and stroke.

Malignant melanoma is a tumor characterized by the uncontrolled proliferation of melanocytes, mainly in skin, but also in eyes. Its incidence is rising each year. To improve the diagnosis and treatment of the tumor, it is essential to develop new effective methods to early detect and characterize melanoma. Previously, we demonstrated in a single-shot study that it was possible to map free radicals of melanin pigments using an electron paramagnetic resonance (EPR)-based method. Furthermore, we demonstrated that X-Band (9 GHz) EPR spectrometry was an accurate tool to assess the growth stage of a pigmented tumor. The aim of the present study was to investigate the ability of EPR imaging to detect and localize melanin pigments inside melanin phantoms, B16 melanoma tumor models and resected human melanomas. We show that EPR can provide an accurate image of synthetic samples, both in terms of shape and size, with errors always lower than 10% compared to the real size. Regarding melanoma studies, the ability of EPR imaging to map accurately the melanoma was depending on the concentration of melanin in the sample, which is proportional to the growth stage of the tumor and the consequent signal-to-noise ratio (SNR) provided by the EPR signal intensity. This led us to define an operational concept, considering SNR and interferences with other EPR signals, to determine when EPR imaging was feasible.

In vivo or ex vivo electron paramagnetic resonance imaging (EPRI) is a powerful technique for determining the spatial distribution of free radicals and other paramagnetic species in living organs and tissues. However, applications of EPRI have been limited by long projection acquisition times and the consequent fact that rapid gated EPRI was not possible. Hence in vivo EPRI typically provided only time-averaged information. In order to achieve direct gated EPRI, a fast EPR acquisition scheme was developed to decrease EPR projection acquisition time down to 10–20 ms, along with corresponding software and instrumentation to achieve fast gated EPRI of the isolated beating heart with submillimeter spatial resolution in as little as 2–3 min. Reconstructed images display temporal and spatial variations of the free-radical distribution, anatomical structure, and contractile function within the rat heart during the cardiac cycle. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Electron paramagnetic resonance imaging (EPRI) can be used to noninvasively and quantitatively obtain three-dimensional maps of tumor pO2. The paramagnetic tracer triarylmethyl (TAM), a substituted trityl radical moiety, is not toxic to animals and provides narrow isotropic spectra, which is ideal for in vivo EPR imaging experiments. From the oxygen-induced spectral broadening of TAM, pO2 maps can be derived using EPRI. The instrumentation consists of an EPRI spectrometer and 7T magnetic resonance imaging (MRI) system both operating at a common radiofrequency of 300 MHz. Anatomic images obtained by MRI can be overlaid with pO2 maps obtained from EPRI. With imaging times of less than 3 min, it was possible to monitor the dynamics of oxygen changes in tumor and distinguish chronically hypoxic regions from acutely hypoxic regions. In this article, the principles of pO2 imaging with EPR and some relevant examples of tumor imaging are reviewed.

The suitability of 3-carboxy-2,2,5,5-tetra( 2 H 3 )methyl-[4- 2 H( 1 H)]-3-pyrroline-(1- 15 N)-1-oxyl and its non-deuterated 14 N-containing nitroxide analogue for L-band EPR in vivo imaging has been demonstrated. Both nitroxides exhibit low rates of reduction with ascorbate and slow decay in mice blood and plasma and, according to the EPR data, accumulate in the liver of a living mice within 10–70 min after the injection via tail vein, and then collect in the bladder.

Electron paramagnetic resonance imaging using nitroxides is a powerful method for visualizing the redox status modulated by oxidative stress in vivo. Typically, however, data acquisition times have been too slow to obtain a sufficient number of projections for three-dimensional images, when using continuous wave-electron paramagnetic resonance imager in small rodents, using nitroxides with comparatively short T(2) and a half-life values. Because of improvements in imagers that enable rapid data-acquisition, the feasibility of three-dimensional electron paramagnetic resonance imaging with good quality in mice was tested with nitroxides. Three-dimensional images of mice were obtained at an interval of 15 sec under field scanning of 0.3 sec and with 46 projections in the case of strong electron paramagnetic resonance signals. Three-dimensional electron paramagnetic resonance images of a blood brain barrier-permeable nitroxide, 3-hydroxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl, in the mouse head clearly showed that 3-hydroxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl was distributed within brain tissues, and this was confirmed by MRI observations. Based on the pharmacokinetics of nitroxides in mice, half-life mapping was demonstrated in an ischemia-reperfusion model mouse brain. Inhomogeneous half-lives were clearly mapped pixel-by-pixel in mouse head under oxidative stress by the improved continuous wave-electron paramagnetic resonance imager noninvasively.

Electron paramagnetic resonance imaging (EPRI) using nitroxides is an emergent imaging method for studying in vivo physiology, including O(2) distribution in various tissues. Such imaging capabilities would allow O(2) mapping in tumors and in different brain regions following hypoxia or drug abuse. We have recently demonstrated that the anion of 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (2) can be entrapped in brain tissue to quantitate O(2) concentration in vivo. To increase the sensitivity of O(2) measurement by EPR imaging, we synthesized 3-carboxy-2,2,5,5-tetra((2)H(3))methyl-1-(3,4,4-(2)H(3),1-(15)N)pyrrolidinyloxyl (7). EPR spectroscopic measurements demonstrate that this fully isotopically substituted nitroxide markedly improves signal-to-noise ratio and, therefore, the sensitivity of EPR imaging. The new isotopically substituted nitroxide shows increased sensitivity to changes in O(2) concentration, which will enable more accurate O(2) measurement in tissues using EPRI.

Electron paramagnetic resonance imaging (EPRI) is a new modality for visualizing O2 distribution in tissues, such as the brain after stroke or after administration of drugs of abuse. We have recently shown that 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl [1] is a pro-imaging agent that can cross the blood–brain barrier. After hydrolysis by esterases, the anion of 3-carboxy-2,2,5,5-tetramethyl-1-tetramethyl-1-pyrrolidinyloxyl [2] is trapped in brain tissue. In this study, we investigated the feasibility of using this to map the changes of O2 concentration in mouse brain after focal ischemia. The decrease in tissue O2 concentration in the ischemic region of mouse brain was clearly visualized by EPRI. The hypoxic zone mapped by EPRI was spatially well correlated with the infarction area in the brain imaged by diffusion-weighted magnetic resonance imaging (MRI). Finally, we observed a decrease in the size of the hypoxic region when the mouse breathed higher levels of O2. This finding suggests that EPRI with specifically designed nitroxides is a promising imaging modality for visualizing O2 distribution in brain tissue, especially in an ischemic brain. We believe that this imaging method can be used for monitoring the effects of therapeutic intervention aimed at enhancing brain O2 supply, which is crucial in minimizing brain injury after stroke.

Electron paramagnetic resonance imaging (EPRI) is a relatively recent imaging technique, which provides potentially multidimensional imaging of the spatial distribution of paramagnetic species. Thanks to the use of stable spin probes, low frequency EPR imaging has recently allowed the use of large tissue samples or whole animals in vivo in the field of biology and medicine. It is normally necessary to introduce prior intravenous or intramuscular infusion of stable or slowly metabolizable non-toxic water-soluble paramagnetic materials, or stable implantable particulate materials as spin probes into the system. The classification and research progress of spin probes at present were described briefly. Three important potential approaches in water-soluble paramagnetic materials design including deuterated, site-specific and macromolecular conjugated nitroxides were also investigated.

Chronic hypoxia strongly affects the malignant state and resistance to therapy for tumours. Transient hypoxia has been hypothesized, but not proven to be more deleterious. Electron paramagnetic resonance imaging (EPRI) provides non-invasive, quantitative imaging of static pO2 in vivo. Dynamic EPRI produces pO2 movies, enabling non-invasive assessment of in vivo pO2 changes, such as transient hypoxia. Recent developments have been made to enable Dynamic EPRI. Maximally spaced projection sequencing has been implemented to allow for more accurate and versatile acquisition of EPRI data when studying dynamic systems. Principal component analysis filtering has been employed to enhance SNR. Dynamic EPRI studies will provide temporally resolved oxygen movies necessary to perform in vivo studies of physiologically relevant pO2 changes in tumours. These oxygen movies will allow for the localization/quantification of transient hypoxia and will therefore help to disentangle the relationship between chronic and transient hypoxia, in order to better understand their roles in therapeutic optimization and outcome.

Electron paramagnetic resonance imaging, EPRI, is an emerging in vivo imaging modality that holds a unique promise of quantitatively mapping tissue oxygen distribution noninvasively. Unlike magnetic resonance imaging (MRI), EPRI requires the use of nontoxic biologically compatible spin probes. Many tumors are characterized by a hypoxic core that is highly resistant to radiation and chemotherapeutic treatment. EPRI enables fast noninvasive assessment of tumor hypoxia, re-oxygenation, and tissue redox status. The two main approaches to EPRI are continuous wave, CW electron paramagnetic resonance (EPR) spectroscopy, and time-domain EPR spectroscopy, FT-EPR. The present article describes the current state of the art of radiofrequency CW and time-domain EPR imaging.

Recently, it has been shown that rat hearts subjected to global ischemia generate nitric oxide (NO) and that a significant portion of it is generated by the reduction of nitrite under the acidic and reducing conditions that occur during myocardial ischemia [Zweier, Wang, Samouilov, Kuppusamy, Nature Med. 1, 804-809 (1995)]. In the present study it is further attempted to map the spatial distributions of the NO generation in the ischemic myocardium using L-band electron paramagnetic resonance imaging. Rat hearts were loaded with 10 mM nitrite and subjected to global no-flow ischemia, during which time a series of three-dimensional spatial electron paramagnetic resonance (EPR) images of the distribution of NO were obtained using the NO trap bis(N-methyl-D-glucamine dithiocarbamate)iron(II). The images clearly showed that NO is formed throughout the myocardium. Kinetic experiments showed that maximum NO generation and trapping occur at the midmyocardium and spread out to endocardium and epicardium of the left ventricle. The magnitude of generation in the RV myocardium is four- to fivefold lower than in the LV.

The article presents a modification to the spline deconvolution technique. The method was developed within the framework of electron paramagnetic resonance imaging and is particularly useful in cases of low signal‐to‐noise ratio (S/N) and when the deconvolution kernel is a large fraction (about 50%) of the studied function. The modified spline deconvolution method works directly in the signal space and does not require a low‐pass filter that causes loss of information and limits the resolution as is the case of Fourier deconvolution. The comparison was done with Fourier deconvolution and was based on three parameters that account for resolution, noise, and proportion stability. Experimental tests were done using two nitroxide‐free radicals of different linewidths (0.05 and 0.16 mT, respectively) at different gradient values (between 0.05 and 0.2 mT/m). Modified spline deconvolution gave consistently better results in all the three parameters, particularly at the lower gradient values. For this reason the method is useful in in vivo experiments where the low S/N does not permit use of high gradient values.

This paper presents an apparatus that permits synchronization of the signal acquisition from a moving sample in electron spin resonance imaging experiments. The apparatus has been designed to observe a perfused beating heart and includes all the necessary apparatus to stimulate the heart and to synchronize the signal acquisition on this stimulus. The apparatus is completed by a low-frequency electron paramagnetic resonance bridge operated at 1.5 GHz, a re-entrant cavity for the sample and air coils to obtain the field gradients. Tests were carried out on a phantom consisting of a thin-walled silicon rubber tube of the approximate dimensions of a rat heart. The phantom movements are obtained by inflating and deflating the tube with a peristaltic pump that can be reversed by computer. The acquisitions are taken in synchronization with the pump positions. The hardware used to drive the pump and to synchronize the acquisitions is also described.

This paper presents the preliminary results obtained using an Electron Paramagnetic Resonance imaging apparatus operating at 280 MHz. The acquisition technique and the procedure used to obtain the spin density spatial localization are presented and specimen images of extended samples are given. The accuracy of the images and the spatial resolution are also discussed.

Low frequency (280 MHz) electron paramagnetic resonance spectroscopy has been used to follow uptake, distribution and reduction of the nitroxyl spin label PCA in the rat. No difference of half life was found in seven rats submitted to three administrations of PCA (11.3 +/- 0.4; 11.0 +/- 0.6 and 11.5 +/- 0.7 min). Transversal two-dimensional images of PCA distribution in the rat body were obtained over 6 min by means of field gradients. PCA was observed in three regions by projections along the longitudinal axis of the rat. PCA accumulation was found in the lower abdomen 12 min after the start of the PCA injection.

Electron paramagnetic resonance imaging (EPRI) and EPR spectroscopy of nitroxides have been applied to detect and quantify cytotoxic effects in mammalian cells in vitro Images depicting microscopic viable and nonviable areas in the same multicellular spheroid (a model of solid tumors) have been acquired prior to and following the treatment with an antitumor drug, Adriamycin. The loss of viability in the inner region of the viable rim was detected. Such mapping of the time-course changes of the localization of viable and nonviable cells in the same intact biological object is not possible with routinely used methods to measure viability, such as histological examination. The experimental conditions required for high accuracy and sensitivity of the EPRI of spheroids have been evaluated and directions for further development of this approach are indicated. © 1991 Academic Press, Inc.

Two-dimensional spectral-spatial electron paramagnetic resonance (EPR) imaging was used to measure the spatial distribution of p-phenylenediamine radicals that were generated electrochemically in the EPR cavity. The multi-line EPR spectrum obtained from a spectral slice through the image was in good agreement with the non-gradient spectrum. A spatial slice showed that the radicals were localized in the vicinity of the working electrode.

The incidence of malignant melanoma is increasing at an alarming rate. As the clinical outcome of the disease strongly depends on the localization of the lesion, early detection at the initial stages of development is critical. Here, we suggest spatial characterization of melanoma based on the presence of endogenous stable free radicals in melanin pigments. Taking into account the abundance of these naturally occurring free radicals in proliferating melanocytes and their localization pattern, we hypothesized that electron paramagnetic resonance (EPR) imaging could be a unique tool for mapping melanomas with high sensitivity and high resolution. The potential of EPR to image melanoma samples was demonstrated in vitro in animal and human samples. Using EPR systems operating at low frequency, we were also able to record in vivo EPR spectra and images from the melanin present in a subcutaneous melanoma implanted in a mouse. In addition to the proof-of-concept and the achievement of providing the first non-invasive image of an endogenous radical, this technology may represent a key advance in improving the diagnosis of suspected melanoma lesions. Copyright (c) 2008 John Wiley & Sons, Ltd.

The resolution and signal to noise ratio of EPR imaging and T1-weighted MRI were compared using an identical phantom. Several solutions of nitroxyl contrast agents with different EPR spectral shapes were tested. The feasibility of T1-weighted MRI to detect nitroxyl contrast agents was described. T1-weighted MRI can detect nitroxyl contrast agents with a complicated EPR spectrum easier and quicker; however, T1-weighted MRI has less quantitative ability especially for lipophilic nitroxyl contrast agents, because T1-relaxivity, i.e. accessibility to water, is affected by the hydrophilic/hydrophobic micro-environment of a nitroxyl contrast agent. The less quantitative ability of T1-weighted MRI may not be a disadvantage of redox imaging, which obtains reduction rate of a nitroxyl contrast. Therefore, T1-weighted MRI has a great advantage to check the pharmacokinetics of newly modified and/or designed nitroxyl contrast agents. 2007 Elsevier Inc. All rights reserved.

Electron paramagnetic resonance imaging (EPRI) is a technique that has been used for in vivo oxygen imaging of small animals. In continuous wave (CW) EPRI, the measurement can be interpreted as a sampled 4D Radon transform of the image function. The conventional filtered-backprojection (FBP) algorithm has been used widely for reconstructing images from full knowledge of the Radon transform acquired in CW EPRI. In practical applications of CW EPRI, one often is interested in information only in a region of interest (ROI) within the imaged subject. It is desirable to accurately reconstruct an ROI image only from partial knowledge of the Radon transform because acquisition of the partial data set can lead to considerable reduction of imaging time. The conventional FBP algorithm cannot, however, reconstruct accurate ROI images from partial knowledge of the Radon transform of even dimension. In this work, we describe two new algorithms, which are referred to as the backprojection filtration (BPF) and minimum-data filtered-backprojection (MDFBP) algorithms, for accurate ROI-image reconstruction from a partial Radon transform (or, truncated Radon transform) in CW EPRI. We have also performed numerical studies in the context of ROI-image reconstruction of a synthetic 2D image with density similar to that found in a small animal EPRI. This demonstrates both the inadequacy of the conventional FBP algorithm and the success of BPF and MDFBP algorithms in ROI reconstruction. The proposed ROI imaging approach promises a means to substantially reduce image acquisition time in CW EPRI.

The potential use of electron paramagnetic resonance imaging (EPRI) to obtain physiological information noninvasively is reviewed. EPR, a spectroscopic technique similar to nuclear magnetic resonance (NMR), is useful in detecting and characterizing free radical species. The ability to obtain information about tissue redox and oxygen status using nontoxic free radical spin probes is presented. The capability to encode this information spatially using magnetic field gradients, similar to magnetic resonance imaging (MRI), gives this technique the ability to overlay functional information of tissue with anatomic information. The noninvasive and quantitative nature of EPRI makes it a potentially useful technique for obtaining physiological information from tumors. The requirements for the magnetic field strengths are approximately 600 times lower than that for proton MRI at an identical frequency, making this a low-cost diagnostic tool.

The present work describes our efforts thus far toward the acquisition of quantitative 3D oxygen concentration maps for tumor volumes using electron paramagnetic resonance imaging (EPRI). These maps are derived from 4D spectral-spatial images that show the spatially localized absorption spectra of an introduced molecular probe. The spectral linewidth for each spatial voxel is linearly related to the local oxygen concentration. Shown here are an image of a phantom and an in vivo image of a tumor implanted in the hind leg of a mouse. We aim to acquire the 4D data sets in 15 minutes and to produce images with sub-millimeter resolution and oxygen concentration sensitivity of several torr. Slices through the 4D spectral-spatial images are shown, as well as the respective linewidth maps given by spectral fitting. The spatial distribution and linewidths measured in the phantom image correlate well with a priori expectations. The mouse tumor image shows probe and linewidth distributions that are consistent with the mouse anatomy and physiology, including a sharp distinction between the bladder and leg/tumor signals. These results demonstrate the promise of EPRI for the measurement of in vivo oxygen concentration.

While electron paramagnetic resonance imaging (EPRI) enables spatial mapping of free radicals in the whole body of small animals, it solely visualizes the free-radical distribution and does not typically provide anatomic visualization of the body. However, anatomic registration is often required for meaningful interpretation of the EPRI-derived free-radical images. An approach is reported for whole-body, EPRI-based, free-radical imaging along with proton MRI in mice. EPRI instrumentation with a 750-MHz narrow band microwave bridge and transverse oriented electric field reentrant resonator, with automatic coupling control and automatic tuning control capability, was used to map the spatial distribution of nitroxide free radicals in phantoms and in living mice, while low-field proton MRI at 16 MHz was used to define the anatomic structure to register the EPR images. Small capillary tubes containing an aqueous radical label were used as markers to enable image superimposition. With this coregistration technique, the EPRI free-radical images were precisely registered, enabling assignment of the location of the observed free-radical distribution within the organs of the mice. This technique enabled differentiation of the distribution and metabolism of nitroxide radicals within the major organs and body sites of living mice.

The paper presents a technique for identifying and removing unwanted terms in the field power expansion of multipolar magnets. The technique is based on the measurement of the radial field at the poles of the magnet. The field terms are derived by analytical formulas and used to evaluate the current corrections. This trimming procedure has been tested for a 16‐pole magnet designed for electron paramagnetic resonance imaging and permits a continuous control of the field configuration.

The qualitative equivalence between the Fourier reconstruction (FR) algorithm and the filtered back projection (FBP) algorithm is demonstrated when all the different phase errors that can occur in FR are eliminated. The causes of phase errors are underlined and methods to eliminate them are presented. The practical comparison between FR and FBP has been evaluated on a numerical test image and the results are reported, demonstrating the qualitative equivalence. FR has the advantage of being very computationally efficient. In fact, the time spent to obtain the FR image was 1/20 of that used to obtain the FBP image. Because of the computational efficiency of FR and the good quality of the results obtained, an iterative version of FR has been used to implement the spectral–spatial imaging (SSI) algorithm in the field of electron paramagnetic resonance imaging (EPRI). An experimental example, demonstrating its good performance, is reported.

In the field of electron paramagnetic resonance (EPR) at very low frequenciws, the spectroscopic and imaging applications are strongly linked. A living sample is, in fact, composed of different structures and organs in which the paramagnetic probes can reach different concentrations, be exposed to different local environments, and be reduced at different rates. For this reason, the spectroscopic information from whole body measurements can be misleading because only accurate knowledge of the spatial distribution of the probe is instructive.

EPR imaging with modulated field gradients provides the possibility for obtaining an EPR spectrum in a selected volume. We demonstrate the feasibility of X-band (9.5 GHz) electron paramagnetic resonance (EPR) imaging in skin biopsies of hairless mice. One- (1D) and two-dimensional (2D) EPR images of the persistent free radical di-tertiary-butyl-nitroxide are measured. At a microwave frequency of 9.5 GHz (X-band), 2D images are obtained in skin biopsies with an actual point distinction resolution of 25 microns. In a biological model system, 2D images are measured at L-band frequency (2.0 GHz) with a pixel resolution of 61 microns, and a theoretical spatial resolution of 12.5 microns. In combination with the spin labeling and spin trapping technique, EPR imaging is the most direct approach to analyzing spatial distribution of physicochemical properties in skin, such as membrane fluidity and polarity, as well as detection of free radicals.