High-Contrast and Fast-Removable 19 F-MRI Labels with Perfluoro-tert-Butyl Substituents.

19 F MRI is a unique technique for tracking and quantifying the indicator (19 F-MRI label) in vivo without the use of ionizing radiation. Here we report new 19 F-MRI labels, which are compounds with perfluoro-tert-butyl groups: 1,2-bis(perfluoro-tert-butoxy)ethane (C10 F18 H4 O2 ) and 1,3-bis(perfluoro-tert-butyl)propane (C11 F18 H6 ). Both substances contain 18 equivalent 19 F atoms, constituting 68.67 % and 71.25 % of the molecule, respectively. The emulsions with 19 F molecules were prepared and used in 19 F MRI studies in laboratory rats in vivo. The substances demonstrated high contrast properties, good biological inertness and the ability to be rapidly eliminated from the body. We showed that at a dose of 0.34 mg/g of body weight in rats, the time for complete elimination of C10 F18 H4 O2 and C11 F18 H6 is ∼30 days. The results turned out to be promising for the use of the presented compounds in 19 F MRI applications, especially since they are quite easy to synthesize.

Т1 mapping of rat lungs in 19 F MRI using octafluorocyclobutane.

PURPOSE: To demonstrate the feasibility of using octafluorocyclobutane (OFCB, c-C4 F8 ) for T1 mapping of lungs in 19 F MRI. METHODS: The study was performed at 7 T in three healthy rats and three rats with pulmonary hypertension. To increase the sensitivity of 19 F MRI, a bent-shaped RF coil with periodic metal strips structure was used. The double flip angle method was used to calculate normalized transmitting RF field (B1n + ) maps and for correcting T1 maps built with the variable flip angle (VFA) method. The ultrashort TE pulse sequence was applied for acquiring MR images throughout the study. RESULTS: The dependencies of OFCB relaxation times on its partial pressure in mixtures with oxygen, air, helium, and argon were obtained. T1 of OFCB linearly depended on its partial pressure with the slope of about 0.35 ms/kPa in the case of free diffusion. RF field inhomogeneity leads to distortion of T1 maps built with the VFA method, and therefore to high standard deviation of T1 in these maps. To improve the accuracy of the T1 maps, the B1n + maps were applied for VFA correction. This contributed to a 2-3-fold decrease in the SD of T1 values in the corresponding maps compared with T1 maps calculated without the correction. Three-dimensional T1 maps were obtained, and the mean T1 in healthy rat lungs was 35 ± 10 ms, and in rat lungs with pulmonary hypertension - 41 ± 9 ms. CONCLUSION: OFCB has a spin-rotational relaxation mechanism and can be used for 19 F T1 mapping of lungs. The calculated OFCB maps captured ventilation defects induced by edema.

Design and first implementation of wireless square-shaped transmission line resonators in 1H MRI for small animal studies.

This work is dedicated to the development of a novel design for wireless transmission line resonators (TLRs). The TLRs are often considered as circular-shaped coils made up of two conductive circuits separated by a dielectric layer. We propose a square-shaped TLR design, wherein the coil has two square turns with two symmetrical gaps on each of the conductive layers, and the latter are rotated relative to each other by 90°. The calculation error of the resonant frequency of the square-shaped TLRs is no more than ∼3% of the measured value. The effectiveness of the square-shaped TLR design was evaluated in comparative 1H MRI studies to conventional wireless square loop of the same resonant frequency and with the same-sized inner square of the TLR. The Bruker birdcage was used as a transceiver and as inductively coupled with the wireless coils. We found that the performance of the square-shaped TLR and the square loop is comparable, but the B1+-field generated by the TLR has a wider distribution profile. It was reflected in rat brain studies, when some structures of rat head were not captured by the square loop. Comparative experiments with a standard circular-shaped TLR showed that a signal is predominantly concentrated inside the inner turn of the TLRs. The proposed TLR design can be a promising path to be explored, especially for scanning small objects of study, when the scan area is comparable to the size of the rigid lumped capacitors.

Sex-Dependent Protective Effect of Combined Application of Solubilized Ubiquinol and Selenium on Monocrotaline-Induced Pulmonary Hypertension in Wistar Rats.

Ubiquinol exhibits anti-inflammatory and antioxidant properties. Selenium is a part of a number of antioxidant enzymes. The monocrotaline inducible model of pulmonary hypertension used in this study includes pathological links that may act as an application for the use of ubiquinol with high bioavailability and selenium metabolic products. On day 1, male and female rats were subcutaneously injected with a water-alcohol solution of monocrotaline or only water-alcohol solution. On days 7 and 14, some animals were intravenously injected with either ubiquinol's vehicle or solubilized ubiquinol, or orally with selenium powder daily, starting from day 7, or received both ubiquinol + selenium. Magnetic resonance imaging of the lungs was performed on day 20. Hemodynamic parameters and morphometry were measured on day 22. An increased right ventricle systolic pressure in relation to control was demonstrated in all groups of animals of both sexes, except the group of males receiving the combination of ubiquinol + selenium. The relative mass of the right ventricle did not differ from the control in all groups of males and females receiving either ubiquinol alone or the combination. Magnetic resonance imaging revealed impaired perfusion in almost all animals examined, but pulmonary fibrosis developed in only half of the animals in the ubiquinol group. Intravenous administration of ubiquinol has a protective effect on monocrotaline-induced pulmonary hypertension development resulting in reduced right ventricle hypertrophy, and lung mass. Ubiquinol + selenium administration resulted in a less severe increase in the right ventricle systolic pressure in male rats but not in females 3 weeks after the start of the experiment. This sex-dependent effect was not observed in the influence of ubiquinol alone.

Synergetic Enhancement of Tumor Double-Targeted MRI Nano-Probe.

The conventional targeted delivery of chemotherapeutic and diagnostic agents utilizing nanocarriers is a promising approach for cancer theranostics. Unfortunately, this approach often faces hindered tumor access that decreases the therapeutic index and limits the further clinical translation of a developing drug. Here, we demonstrated a strategy of simultaneously double-targeting the drug to two distinct cites of tumor tissue: the tumor endothelium and cell surface receptors. We used fourth-generation polyamideamine dendrimers modified with a chelated Gd and functionalized with selectin ligand and alpha-fetoprotein receptor-binding peptide. According to the proposed strategy, IELLQAR peptide promotes the conjugate recruitment to the tumor inflammatory microenvironment and enhances extravasation through the interaction of nanodevice with P- and E-selectins expressed by endothelial cells. The second target moiety-alpha-fetoprotein receptor-binding peptide-enhances drug internalization into cancer cells and the intratumoral retention of the conjugate. The final conjugate contained 18 chelated Gd ions per dendrimer, characterized with a 32 nm size and a negative surface charge of around 18 mV. In vitro contrasting properties were comparable with commercially available Gd-chelate: r1 relaxivity was 3.39 for Magnevist and 3.11 for conjugate; r2 relaxivity was 5.12 for Magnevist and 4.81 for conjugate. By utilizing this dual targeting strategy, we demonstrated the increment of intratumoral accumulation, and a remarkable enhancement of antitumor effect, resulting in high-level synergy compared to monotargeted conjugates. In summary, the proposed strategy utilizing tumor tissue double-targeting may contribute to an enhancement in drug and diagnostic accumulation in aggressive tumors.

Imaging Capabilities of the ¹H-X-Nucleus Metamaterial-Inspired Multinuclear RF-Coil.

In this paper, we present the initial experimental investigation of a two-coil receive/transmit design for small animals imaging at 7T MRI. The system uses a butterfly-type coil tuned to 300 MHz for scanning the 1H nuclei and a non-resonant loop antenna with a metamaterial-inspired resonator with the ability to tune over a wide frequency range for X-nuclei. 1H, 31P, 23Na and 13C, which are of particular interest in biomedical MRI, were selected as test nuclei in this work. Coil simulations show the two parts of the radiofrequency (RF) assembly to be decoupled and operating independently due to the orthogonality of the excited RF transverse magnetic fields. Simulations and phantom experimental imaging show sufficiently homogeneous transverse transmit RF fields and tuning capabilities for the pilot multiheteronuclear experiments.

Three-dimensional fast single-point macromolecular proton fraction mapping of the human brain at 0.5 Tesla.

Fast single-point macromolecular proton fraction (MPF) mapping is a recent magnetic resonance imaging (MRI) method enabling quantitative assessment of myelin content in neural tissues. To date, the reported technical implementations of MPF mapping utilized high-field MRI equipment (1.5 T or higher), while low-field applications might pose challenges due to signal-to-noise ratio (SNR) limitations and short T1 . This study aimed to evaluate the feasibility of MPF mapping of the human brain at 0.5 T. The three-dimensional MPF mapping protocol was implemented according to the single-point synthetic-reference method, which includes three spoiled gradient-echo sequences providing proton density, T1 , and magnetization transfer contrast weightings. Whole-brain MPF maps were obtained from three healthy volunteers with spatial resolution of 1.5×1.5×2 mm3 and the total scan time of 19 minutes. MPF values were measured in a series of white and gray matter structures and compared with literature data for 3 T magnetic field. MPF maps enabled high contrast between white and gray matter with notable insensitivity to paramagnetic effects in iron-rich structures, such as globus pallidus, substantia nigra, and dentate nucleus. MPF values at 0.5 T appeared in close agreement with those at 3 T. This study demonstrates the feasibility of fast MPF mapping with low-field MRI equipment and the independence of brain MPF values of magnetic field. The presented results confirm the utility of MPF as an absolute scale for MRI-based myelin content measurements across a wide range of magnetic field strengths and extend the applicability of fast MPF mapping to inexpensive low-field MRI hardware.

19 F MRI of human lungs at 0.5 Tesla using octafluorocyclobutane.

PURPOSE: The aim of this study was to demonstrate the feasibility of fluorine-19 (19 F) MRI of the human lungs using octafluorocyclobutane (OFCB, C4 F8 ). This gas has 8 magnetically equivalent fluorine nuclei and relatively long T1 and T2 (˜50 ms), which render it suitable as an MRI contrast agent. Previous experiments in small laboratory animals showed that OFCB could be successfully used as an alternative to the gases often used for 19 F MRI (sulfur hexafluoride and perfluoropropane). METHODS: One male volunteer participated in this study. Immediately before an MRI scan, the volunteer inhaled the gas mixture-80% OFCB with 20% oxygen-and held his breath. Experiments were performed on a 0.5T whole-body MR scanner with a customized transmit-receive coil tuned at 19 F frequency. Fast spin echo in 2D and 3D modes was used for image acquisition. 2D images were obtained with in-plane resolution of 10 × 10 mm2 without slice selection. 3D images were obtained with the voxel size of 10 × 10 × 30 mm2 . Breath-hold duration was 20 s for 2D and 40 s for 3D imaging, respectively. RESULTS: Anatomically consistent 19 F MR images of the human lungs were obtained with SNR around 50 in 2D mode and 20 in 3D mode. 3D volumetric images of the lungs were reconstructed and provided physiologically reasonable volume estimates. CONCLUSION: The application of OFCB enables informative 19 F lung imaging even at low magnetic field strengths. The OFCB gas shows promise as an inhalable contrast agent for fluorine lung MRI and has a potential for clinical translation.

Application of copper plates for frequency tuning of surface wired and wireless MRI coils.

This study shows how a copper plate could be used for frequency tuning of surface wired and wireless MRI coils. For this purpose, it is proposed to place the copper plate directly on their conducting circuit. This leads to increase in the resonance frequency of coils. The effect is most perceptible if the copper plate is comparable in size to the conducting circuit of radiofrequency (RF) coil. The experimental work was performed on a 7.05 T MR scanner using surface MRI coils operating on different resonance frequencies: 1H (300 MHz), 31P (121 MHz), 23Na (79 MHz), 13C (75 MHz). Application of copper plate for frequency tuning of wireless multi-turn multi-gap transmission line resonator (MTMG-TLR) was considered for the first time. The proposed method can be claimed if the nominal variable inductance or capacitance is not enough for tuning the resonance frequency of the MRI coil to a higher frequency range.

Computation of the resonance frequencies of the transmission line resonators used in MRI.

Stripline high frequency resonators or transmission line resonators (TLRs) manufactured as concentric RF coils at the opposite sides of a dielectric sheet serve as wireless self-resonant transmitters-receivers in MRI. Owing to their high quality factor relative to traditional RF coils composed of bulk inductor and capacitors, frequency selectivity of TLRs is high, making them promising elements for single-nucleus MRI. However, the computation of their resonance frequencies is cumbersome, and numerous mathematical mistakes and typos in publications lead to incorrect results. The present publication is the first to summarize the corrected formulas for computations and presents comparison of such computations to real measurements.

Realization of 19F MRI oximetry method using perfluorodecalin.

OBJECTIVE: To identify the technical aspects of the potential use of clinically approved perfluorodecalin (PFD, C10F18) for 19F magnetic resonance imaging (MRI) oximetry method at high magnetic field 7.05 T. MATERIALS AND METHODS: 19F T1 measurements were made on a set of PFD samples with different oxygen contents (0%, 21%, and 100%) at room (21 °C) and body temperature (37 °C). In vivo MRI studies were carried out on one healthy rat and two rats with C6 brain glioma. RESULTS: The selective excitation of the magnetically equivalent 19F nuclei of CF2 groups of trans-isomer of PFD, which give a doublet at a frequency of about - 140 ppm (in relation the chemical shift of trifluoroacetic acid, which is - 76.55 ppm) should be done for correct implementation of 19F MRI oximetry method. The amount of PFD equal to 30 µl is the optimal for obtaining reliable data on the measured T1 values. In this case, the standard deviation of T1 does not exceed 5%. In vivo MRI studies showed that the values of the partial pressure of oxygen (pO2) decrease from normal values of about 38 mmHg (healthy brain) to almost 0 mmHg at the last stage of tumor growth. CONCLUSION: The study showed the feasibility of the successful application of PFD for 19F MRI oximetry method.

Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic⁻Ischemic Brain Injury.

Neonatal hypoxia⁻ischemia is one of the main causes of mortality and disability of newborns. To study the mechanisms of neonatal brain cell damage, we used a model of neonatal hypoxia⁻ischemia in seven-day-old rats, by annealing of the common carotid artery with subsequent hypoxia of 8% oxygen. We demonstrate that neonatal hypoxia⁻ischemia causes mitochondrial dysfunction associated with high production of reactive oxygen species, which leads to oxidative stress. Targeted delivery of antioxidants to the mitochondria can be an effective therapeutic approach to treat the deleterious effects of brain hypoxia⁻ischemia. We explored the neuroprotective properties of the mitochondria-targeted antioxidant SkQR1, which is the conjugate of a plant plastoquinone and a penetrating cation, rhodamine 19. Being introduced before or immediately after hypoxia⁻ischemia, SkQR1 affords neuroprotection as judged by the diminished brain damage and recovery of long-term neurological functions. Using vital sections of the brain, SkQR1 has been shown to reduce the development of oxidative stress. Thus, the mitochondrial-targeted antioxidant derived from plant plastoquinone can effectively protect the brain of newborns both in pre-ischemic and post-stroke conditions, making it a promising candidate for further clinical studies.

Small-animal, whole-body imaging with metamaterial-inspired RF coil.

Particular applications in preclinical magnetic resonance imaging require the entire body of an animal to be imaged with sufficient quality. This is usually performed by combining regions scanned with small coils with high sensitivity or long scans using large coils with low sensitivity. Here, a metamaterial-inspired design employing a parallel array of wires operating on the principle of eigenmode hybridization was used to produce a small-animal imaging coil. The coil field distribution responsible for the coil field of view and sensitivity was simulated in an electromagnetic simulation package and the coil geometrical parameters were optimized for whole-body imaging. A prototype coil was then manufactured and assembled using brass telescopic tubes with copper plates as distributed capacitance. Its field distribution was measured experimentally using the B1+ mapping technique and was found to be in close correspondence with the simulated results. The coil field distribution was found to be suitable for large field of view small-animal imaging and the coil image quality was compared with a commercially available coil by whole-body scanning of living mice. Signal-to-noise measurements in living mice showed higher values than those of a commercially available coil with large receptive fields, and rivalled the performance of small receptive field and high-sensitivity coils. The coil was deemed to be suitable for some whole-body, small-animal preclinical applications.

Neuroprotective Effects of Mitochondria-Targeted Plastoquinone and Thymoquinone in a Rat Model of Brain Ischemia/Reperfusion Injury.

We explored the neuroprotective properties of natural plant-derived antioxidants plastoquinone and thymoquinone (2-demethylplastoquinone derivative) modified to be specifically accumulated in mitochondria. The modification was performed through chemical conjugation of the quinones with penetrating cations: Rhodamine 19 or tetraphenylphosphonium. Neuroprotective properties were evaluated in a model of middle cerebral artery occlusion. We demonstrate that the mitochondria-targeted compounds, introduced immediately after reperfusion, possess various neuroprotective potencies as judged by the lower brain damage and higher neurological status. Plastoquinone derivatives conjugated with rhodamine were the most efficient, and the least efficiency was shown by antioxidants conjugated with tetraphenylphosphonium. Antioxidants were administered intraperitoneally or intranasally with the latter demonstrating a high level of penetration into the brain tissue. The therapeutic effects of both ways of administration were similar. Long-term administration of antioxidants in low doses reduced the neurological deficit, but had no effect on the volume of brain damage. At present, cationic decylrhodamine derivatives of plastoquinone appear to be the most promising anti-ischemic mitochondria-targeted drugs of the quinone family. We suggest these antioxidants could be potentially used for a stroke treatment.

Magnetic resonance spectroscopy of the ischemic brain under lithium treatment. Link to mitochondrial disorders under stroke.

Recent evidence suggests that mitochondria are one of the main factors in the pathogenesis in different organs including brain. The pathogenesis after brain damage is caused not only by the change in bioenergetics, but also involves impairment of alternative functions of mitochondria, particularly those related to the control of cell death. In this study we evaluated partial metabolic pathways under the simulation of a stroke by using the occlusion of the middle cerebral artery in rats. The analysis shows that the induced switch to a non-oxidative energy metabolism (glycolysis) due to the block of tissue oxygen supply does not ensure the adequate supply of the tissue with ATP. Moreover, the well-known acidification of the ischemic tissue is not associated with the so-called traditionally and incorrectly considered "lactic acidosis" (the generation of lactate from glucose by itself does not lead to excessive generation of protons), but occurs because of the consumption of tissue ATP under its reduced resynthesis. Incubation of mitochondria isolated from normal rat brain at neutral and slightly acidic pH, mimicking the intracellular pH of normal and ischemic tissues correspondingly, revealed serious changes in mitochondrial bioenergetics, partially reflected in the magnitude of respiratory control and the basal and maximally stimulated respiration rates. Measurement of available metabolites by (1)H MR spectra of normal and ischemia-damaged brains showed a significant increase in lactate and myo-inositol and a moderate decrease in N-acetylaspartate 24h after reperfusion. Remarkably, the administration of lithium chloride in the reperfusion phase normalized the levels of metabolites. Moreover, the introduction of lithium salts (chloride or succinate) in the bloodstream, restored after ischemia, reduced both the size of the ischemia-induced brain damage and the degree of brain swelling. Besides, post-ischemic introduction of lithium salts largely restored the neurological status of the animal.