19 F VT NMR: Novel Tm3+ and Ce3+ Complexes Provide New Insight into Temperature Measurement Using Molecular Sensors.

In the past few decades, magnetic resonance spectroscopy (MRS) and MR imaging (MRI) have developed into a powerful non-invasive tool for medical diagnostic and therapy. Especially 19 F MR shows promising potential because of the properties of the fluorine atom and the negligible background signals in the MR spectra. The detection of temperature in a living organism is quite difficult, and usually external thermometers or fibers are used. Temperature determination via MRS needs temperature-sensitive contrast agents. This article reports first results of solvent and structural influences on the temperature sensitivity of 19 F NMR signals of chosen molecules. By using this chemical shift sensitivity, a local temperature can be determined with a high precision. Based on this preliminary study, we synthesized five metal complexes and compared the results of all variable temperature measurements. It is shown that the highest 19 F MR signal temperature dependence is detectable for a fluorine nucleus in a Tm3+ -complex.

19 F VT NMR: Novel Tm3+ and Ce3+ Complexes Provide New Insight into Temperature Measurement Using Molecular Sensors.

The front cover artwork is provided by Dr. Markus Plaumann's group at the Otto-von-Guericke University Magdeburg. The image shows the investigated 19 F labeled molecules, which can be used as temperature MR-sensors in different solvents. The direction of the chemical shift change is strongly solvent dependent. Read the full text of the Research Article at 10.1002/cphc.202300057.

Organic Fluorine Compounds and Their Uses as Molecular MR-Based Temperature Sensors.

The interest in fluorinated substances has increased significantly in recent decades due to their diverse properties and possible uses. An important analytical method in this context is NMR spectroscopy, which provides information on the structure as well as on intermolecular interactions or generally on changes in the environment of the nucleus under consideration. A physical quantity that is of great importance in most studies is temperature. However, this is not always easy, e. g. in shielded systems or within an organism. However, the application potential in chemical reactors or in medical diagnosis and therapy is very high and for this reason 13 fluorinated organic compound were chosen for a first 19 F NMR signal temperature sensitivity examination for determination of local temperatures in solution. Polyfluorinated molecules with separate 19 F MR signals are particularly suitable for temperature determination. Those can be serve as internal error-correcting thermometers without the need of a reference substance. Under these conditions, a 19 F MR signal shift of up to 0.03 ppm/K was detectable. Fluorine position and chemical environment were very important for the temperature sensitivity.

Coherent Evolution of Signal Amplification by Reversible Exchange in Two Alternating Fields (alt-SABRE).

Parahydrogen (pH2 ) is a convenient and cost-efficient source of spin order to enhance the magnetic resonance signal. Previous work showed that transient interaction of pH2 with a metal organic complex in a signal amplification by reversible exchange (SABRE) experiment enabled more than 10 % polarization for some 15 N molecules. Here, we analyzed a variant of SABRE, consisting of a magnetic field alternating between a low field of ∼1 µT, where polarization transfer is expected to take place, and a higher field >50 µT (alt-SABRE). These magnetic fields affected the amplitude and frequency of polarization transfer. Deviation of a lower magnetic field from a "perfect" condition of level anti-crossing increases the frequency of polarization transfer that can be exploited for polarization of short-lived transient SABRE complexes. Moreover, the coherences responsible for polarization transfer at a lower field persisted during magnetic field variation and continued their spin evolution at higher field with a frequency of 2.5 kHz at 54 µT. The latter should be taken into consideration for an efficient alt-SABRE. Theoretical and experimental findings were exemplified with Iridium N-heterocyclic carbene SABRE complex and 15 N-acetonitrole, where a 30 % higher 15 N polarization with alt-SABRE compared to common SABRE was reached.

Multiple Quantum Coherences Hyperpolarized at Ultra-Low Fields.

The development of hyperpolarization technologies enabled several yet exotic NMR applications at low and ultra-low fields (ULF), where without hyperpolarization even the detection of a signal from analytes is a challenge. Herein, we present a method for the simultaneous excitation and observation of homo- and heteronuclear multiple quantum coherences (from zero up to the third-order), which give an additional degree of freedom for ULF NMR experiments, where the chemical shift variation is negligible. The approach is based on heteronuclear correlated spectroscopy (COSY); its combination with a phase-cycling scheme allows the selective observation of multiple quantum coherences of different orders. The nonequilibrium spin state and multiple spin orders are generated by signal amplification by reversible exchange (SABRE) and detected at ULF with a superconducting quantum interference device (SQUID)-based NMR system.

Low-cost LED-based Photo-CIDNP Enables Biocompatible Hyperpolarization of 19 F for NMR and MRI at 7†T and 4.7†T.

Substrates containing 19 F can serve as background-free reporter molecules for NMR and MRI. However, in vivo applications are still limited due to the lower signal-to-noise ratio (SNR) when compared with 1 H NMR. Although hyperpolarization can increase the SNR, to date, only photo-chemically induced dynamic nuclear polarization (photo-CIDNP) allows for hyperpolarization without harmful metal catalysts. Photo-CIDNP was shown to significantly enhance 19 F NMR signals of 3-fluoro-DL-tyrosine in aqueous solution using flavins as photosensitizers. However, lasers were used for photoexcitation, which is expensive and requires appropriate protection procedures in a medical or lab environment. Herein, we report 19 F MR hyperpolarization at 4.7 T and 7 T with a biocompatible system using a low-cost and easy-to-handle LED-based set-up. First hyperpolarized 19 F MR images could be acquired, because photo-CIDNP enabled repetitive hyperpolarization without adding new substrates.

Mapping fine-scale anatomy of gray matter, white matter, and trigeminal-root region applying spherical deconvolution to high-resolution 7-T diffusion MRI.

OBJECTIVES: We assessed the use of high-resolution ultra-high-field diffusion magnetic resonance imaging (dMRI) to determine neuronal fiber orientation density functions (fODFs) throughout the human brain, including gray matter (GM), white matter (WM), and small intertwined structures in the cerebellopontine region. MATERIALS AND METHODS: We acquired 7-T whole-brain dMRI data of 23 volunteers with 1.4-mm isotropic resolution; fODFs were estimated using constrained spherical deconvolution. RESULTS: High-resolution fODFs enabled a detailed view of the intravoxel distributions of fiber populations in the whole brain. In the brainstem region, the fODF of the extra- and intrapontine parts of the trigeminus could be resolved. Intrapontine trigeminal fiber populations were crossed in a network-like fashion by fiber populations of the surrounding cerebellopontine tracts. In cortical GM, additional evidence was found that in parts of primary somatosensory cortex, fODFs seem to be oriented less perpendicular to the cortical surface than in GM of motor, premotor, and secondary somatosensory cortices. CONCLUSION: With 7-T MRI being introduced into clinical routine, high-resolution dMRI and derived measures such as fODFs can serve to characterize fine-scale anatomic structures as a prerequisite to detecting pathologies in GM and small or intertwined WM tracts.

Increasing the spatial resolution and sensitivity of magnetic resonance elastography by correcting for subject motion and susceptibility-induced image distortions.

PURPOSE: To improve the resolution of elasticity maps by adapting motion and distortion correction methods for phase-based magnetic resonance imaging (MRI) contrasts such as magnetic resonance elastography (MRE), a technique for measuring mechanical tissue properties in vivo. MATERIALS AND METHODS: MRE data of the brain were acquired with echo-planar imaging (EPI) at 3T (n = 14) and 7T (n = 18). Motion and distortion correction parameters were estimated using the magnitude images. The real and imaginary part of the complex MRE data were corrected separately and recombined. The width of the point-spread function (PSF) and the position variability were calculated. The images were normalized to the Montreal Neurological Institute (MNI) anatomical template. The gray-to-white matter separability of the elasticity maps was tested. RESULTS: Motion correction sharpened the |G*| maps as demonstrated by a narrowing of the PSF by 0.78 ± 0.51 mm at 7T and 0.52 ± 0.63 mm at 3T. The amount of individual head motion during MRE acquisition correlated with the decrease in the width of the PSF at 7T (r = 0.53, P = 0.025) and at 3T (r = 0.69, P = 0.006) and with the increase of gray-to-white matter separability after motion correction at 7T (r = 0.64, P = 0.0039) and at 3T (r = 0.57, P = 0.0319). Improved spatial accuracy after distortion correction results in a significant increase in separability of gray and white matter stiffness (P = 0.0067), especially in inferior parts of the brain suffering from strong B0 inhomogeneities. CONCLUSION: We demonstrate that our method leads to sharper images and higher spatial accuracy, raising the prospect of the investigation of smaller brain areas with increased sensitivity in studies using MRE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:134-141.

A form-fitted three channel (31) P, two channel (1) H transceiver coil array for calf muscle studies at 7 T.

PURPOSE: To enhance sensitivity and coverage for calf muscle studies, a novel, form-fitted, three-channel phosphorus-31 ((31) P), two-channel proton ((1) H) transceiver coil array for 7 T MR imaging and spectroscopy is presented. METHODS: Electromagnetic simulations employing individually generated voxel models were performed to design a coil array for studying nonpathological muscle metabolism. Static phase combinations of the coil elements' transmit fields were optimized based on homogeneity and efficiency for several voxel models. The best-performing design was built and tested both on phantoms and in vivo. RESULTS: Simulations revealed that a shared conductor array for (31) P provides more robust interelement decoupling and better homogeneity than an overlap array in this configuration. A static B1 (+) shim setting that suited various calf anatomies was identified and implemented. Simulations showed that the (31) P array provides signal-to-noise ratio (SNR) benefits over a single loop and a birdcage coil of equal radius by factors of 3.2 and 2.6 in the gastrocnemius and by 2.5 and 2.0 in the soleus muscle. CONCLUSION: The performance of the coil in terms of B1 (+) and achievable SNR allows for spatially localized dynamic (31) P spectroscopy studies in the human calf. The associated higher specificity with respect to nonlocalized measurements permits distinguishing the functional responses of different muscles.

High-resolution mechanical imaging of the human brain by three-dimensional multifrequency magnetic resonance elastography at 7T.

Magnetic resonance elastography (MRE) is capable of measuring the viscoelastic properties of brain tissue in vivo. However, MRE is still limited in providing high-resolution maps of mechanical constants. We therefore introduce 3D multifrequency MRE (3DMMRE) at 7T magnetic field strength combined with enhanced multifrequency dual elasto-visco (MDEV) inversion in order to achieve high-resolution elastographic maps of in vivo brain tissue with 1mm(3) resolution. As demonstrated by phantom data, the new MDEV-inversion method provides two high resolution parameter maps of the magnitude (|G*|) and the phase angle (ϕ) of the complex shear modulus. MDEV inversion applied to cerebral 7T-3DMMRE data of five healthy volunteers revealed structures of brain tissue in greater anatomical details than previous work. The viscoelastic properties of cortical gray matter (GM) and white matter (WM) could be differentiated by significantly lower values of |G*| and ϕ in GM (21% [P<0.01]; 8%, [P<0.01], respectively) suggesting that GM is significantly softer and less viscous than WM. In conclusion, 3DMMRE at ultrahigh magnetic fields and MDEV inversion open a new window into characterizing the mechanical structure of in vivo brain tissue and may aid the detection of various neurological disorders based on their effects to mechanical tissue properties.

Parahydrogen-induced polarization of carboxylic acids: a pilot study of valproic acid and related structures.

Parahydrogen-induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non-Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. (13)C), thus improving the signal-to-noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the (1)H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized (13)C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP-based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration.

Synthesis, solid-state NMR characterization, and application for hydrogenation reactions of a novel Wilkinson's-type immobilized catalyst.

Silica nanoparticles (SiNPs) were chosen as a solid support material for the immobilization of a new Wilkinson's-type catalyst. In a first step, polymer molecules (poly(triphenylphosphine)ethylene (PTPPE); 4-diphenylphosphine styrene as monomer) were grafted onto the silica nanoparticles by surface-initiated photoinferter-mediated polymerization (SI-PIMP). The catalyst was then created by binding rhodium (Rh) to the polymer side chains, with RhCl3⋅x H2O as a precursor. The triphenylphosphine units and rhodium as Rh(I) provide an environment to form Wilkinson's catalyst-like structures. Employing multinuclear ((31)P, (29)Si, and (13)C) solid-state NMR spectroscopy (SSNMR), the structure of the catalyst bound to the polymer and the intermediates of the grafting reaction have been characterized. Finally, first applications of this catalyst in hydrogenation reactions employing para-enriched hydrogen gas (PHIP experiments) and an assessment of its leaching properties are presented.

Dipolar induced para-hydrogen-induced polarization.

Analytical expressions for the signal enhancement in solid-state PHIP NMR spectroscopy mediated by homonuclear dipolar interactions and single pulse or spin-echo excitation are developed and simulated numerically. It is shown that an efficient enhancement of the proton NMR signal in solid-state NMR studies of chemisorbed hydrogen on surfaces is possible. Employing typical reaction efficacy, enhancement-factors of ca. 30-40 can be expected both under ALTADENA and under PASADENA conditions. This result has important consequences for the practical application of the method, since it potentially allows the design of an in-situ flow setup, where the para-hydrogen is adsorbed and desorbed from catalyst surfaces inside the NMR magnet.

On the relationship between viscoelasticity and water diffusion in soft biological tissues.

Magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) are complementary imaging techniques that detect disease based on viscoelasticity and water mobility, respectively. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering the clinical translation of combined DWI-MRE markers. We used DWI-MRE to study 129 biomaterial samples including native and cross-linked collagen, glycosaminoglycans (GAGs) with different sulfation levels, and decellularized specimens of pancreas and liver, all with different proportions of solid tissue, or solid fractions. We developed a theoretical framework of the relationship between mechanical loss and tissue-water mobility based on two parameters, solid and fluid viscosity. These parameters revealed distinct DWI-MRE property clusters characterizing weak, moderate, and strong water-network interactions. Sparse networks interacting weakly with water, such as collagen or diluted decellularized tissue, resulted in marginal changes in water diffusion over increasing solid viscosity. In contrast, dense networks with larger solid fractions exhibited both free and hindered water diffusion depending on the polarity of the solid components. For example, polar and highly sulfated GAGs as well as native soft tissues hindered water diffusion despite relatively low solid viscosity. Our results suggest that two fundamental properties of tissue networks, solid fraction and network polarity, critically influence solid and fluid viscosity in biological tissues. Since clinical DWI and MRE are sensitive to these viscosity parameters, the framework we present here can be used to detect tissue remodeling and architectural changes in the setting of diagnostic imaging. STATEMENT OF SIGNIFICANCE: The viscoelastic properties of biological tissues provide a wealth of information on the vital state of cells and host matrix. Combined measurement of viscoelasticity and water diffusion by medical imaging is sensitive to tissue microarchitecture. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering full exploitation of these properties as a combined clinical biomarker. Therefore, we analyzed the parameter space accessible by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) and developed a theoretical framework for the relationship between water mobility and mechanical parameters in biomaterials. Our theory of solid material properties related to particle motion can be translated to clinical radiology using clinically established MRE and DWI.

Parahydrogen-induced polarization transfer to 19F in perfluorocarbons for 19F†NMR spectroscopy and MRI.

Fluorinated substances are important in chemistry, industry, and the life sciences. In a new approach, parahydrogen-induced polarization (PHIP) is applied to enhance (19)F MR signals of (perfluoro-n-hexyl)ethene and (perfluoro-n-hexyl)ethane. Unexpectedly, the end-standing CF3 group exhibits the highest amount of polarization despite the negligible coupling to the added protons. To clarify this non-intuitive distribution of polarization, signal enhancements in deuterated chloroform and acetone were compared and (19)F-(19)F NOESY spectra, as well as (19)F T1 values were measured by NMR spectroscopy. By using the well separated and enhanced signal of the CF3 group, first (19)F MR images of hyperpolarized linear semifluorinated alkenes were recorded.

Ultra-high field MRI for primate imaging using the travelling-wave concept.

OBJECT: Ultra-high field (UHF) neuroimaging is usually conducted with volume transmit (Tx) and phased array receive (Rx) coils, both tightly enclosing the object. The travelling-wave (TW) concept allows a remote excitation offering more flexible experimental setups. To investigate the feasibility of primate MRI in horizontal UHF MRI, we first compared the distribution of the electromagnetic fields in an oil phantom and then verified the concept with an in vivo experiment. MATERIALS AND METHODS: In the phantom experiments an in-house circularly polarized hybrid birdcage coil and a self-developed patch antenna were used for Tx and an eight-element phased array antenna for Rx. B1+ fields were calculated and measured for both approaches. For in vivo experiments the Rx part was replaced with an optimized three-element phased array head coil. The SAR was calculated using field simulation. RESULTS: In the phantom the field distribution was homogenous in a central volume of interest of about 10 cm diameter. The TW concept showed a slightly better homogeneity. Examination of a female crab-eating macaque led to homogeneous high-contrast images with a good delineation of anatomical details. CONCLUSION: The TW concept opens up a new approach for MRI of medium-sized animals in horizontal UHF scanners.

Two fluorinated thulium complexes as molecular temperature sensors in MR applications.

19F-based magnetic resonance is a powerful tool to overcome several difficulties of standard 1H MR. We present the syntheses and characterization (including cell viability and stability tests) of two Tm3+ complexes. Both complexes allow the detection of temperature (ΔCT = -0.2319 ppm K-1 and -0.2122 ppm K-1) without a reference compound.

Parahydrogen induced polarization in face of keto-enol tautomerism: proof of concept with hyperpolarized ethanol.

Hyperpolarization (HP) techniques are increasingly important in magnetic resonance imaging (MRI) and spectroscopy (MRS). HP methods have the potential to overcome the fundamentally low sensitivity of magnetic resonance (MR). A breakthrough of HP-MR in life sciences and medical applications is still limited by the small number of accessible, physiologically relevant substrates. Our study presents a new approach to extend PHIP to substrates that primarily cannot be hyperpolarized due to a steady intramolecular re-arrangement, the so-called keto-enol tautomerism. To overcome this obstacle we exploited the fact that instead of the instable enol form the corresponding stable ester can be used as a precursor molecule. This strategy now enables the hydrogenation which is required to apply the standard PHIP procedure. As the final step a hydrolysis is necessary to release the hyperpolarized target molecule. Using this new approach ethanol was successfully hyperpolarized for the first time. It may therefore be assumed that the outlined multi-step procedure can be used for other keto-enol tautomerized substances thereby opening the application of PHIP to a multitude of molecules relevant to analyzing metabolic pathways.

Time domain para hydrogen induced polarization.

Para hydrogen induced polarization (PHIP) is a powerful hyperpolarization technique, which increases the NMR sensitivity by several orders of magnitude. However the hyperpolarized signal is created as an anti-phase signal, which necessitates high magnetic field homogeneity and spectral resolution in the conventional PHIP schemes. This hampers the application of PHIP enhancement in many fields, as for example in food science, materials science or MRI, where low B(0)-fields or low B(0)-homogeneity do decrease spectral resolution, leading to potential extinction if in-phase and anti-phase hyperpolarization signals cannot be resolved. Herein, we demonstrate that the echo sequence (45°-τ-180°-τ) enables the acquisition of low resolution PHIP enhanced liquid state NMR signals of phenylpropiolic acid derivatives and phenylacetylene at a low cost low-resolution 0.54 T spectrometer. As low field TD-spectrometers are commonly used in industry or biomedicine for the relaxometry of oil-water mixtures, food, nano-particles, or other systems, we compare two variants of para-hydrogen induced polarization with data-evaluation in the time domain (TD-PHIP). In both TD-ALTADENA and the TD-PASADENA strong spin echoes could be detected under conditions when usually no anti-phase signals can be measured due to the lack of resolution. The results suggest that the time-domain detection of PHIP-enhanced signals opens up new application areas for low-field PHIP-hyperpolarization, such as non-invasive compound detection or new contrast agents and biomarkers in low-field Magnetic Resonance Imaging (MRI). Finally, solid-state NMR calculations are presented, which show that the solid echo (90y-τ-90x-τ) version of the TD-ALTADENA experiment is able to convert up to 10% of the PHIP signal into visible magnetization.

New investigations of technical rhodium and iridium catalysts in homogeneous phase employing para-hydrogen induced polarization.

It is shown that the para-hydrogen induced polarization (PHIP) phenomenon in homogenous solution containing the substrate styrene is also observable employing simple inorganic systems of the form MCl(3)·xH(2)O (M=Rh, Ir) as catalyst. Such observation confirms that already very simple metal complexes enable the creation of PHIP signal enhancement in solution. This opens up new pathways to increase the sensitivity of NMR and MRT by PHIP enhancement using cost-effective catalysts and will be essential for further mechanistic studies of simple transition metal systems.