Mixture and dissolution of laser polarized noble gases: Spectroscopic and imaging applications

Hyperpolarized 1H long lived states originating from parahydrogen accessed by rf irradiation

Hyperpolarization has found many applications in Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI). However, its usage is still limited to the observation of relatively fast processes because of its short lifetimes. This issue can be circumvented by storing the hyperpolarization in a slowly relaxing singlet state. Symmetrical molecules hyperpolarized by Parahydrogen Induced Hyperpolarization (PHIP) provide a straightforward access to hyperpolarized singlet states because the initial parahydrogen singlet state is preserved at almost any magnetic field strength. In these systems, which show a remarkably long 1H singlet state lifetime of several minutes, the conversion of t…

Magnetic resonance imaging of dissolved hyperpolarized 129Xe using a membrane-based continuous flow system.

Abstract A technique for continuous production of solutions containing hyperpolarized 129Xe is explored for MRI applications. The method is based on hollow fiber membranes which inhibit the formation of foams and bubbles. A systematic analysis of various carrier agents for hyperpolarized 129Xe has been carried out, which are applicable as contrast agents for in vivo MRI. The image quality of different hyperpolarized Xe solutions is compared and MRI results obtained in a clinical as well as in a nonclinical MRI setting are provided. Moreover, we demonstrate the application of 129Xe contrast agents produced with our dissolution method for lung MRI by imaging hyperpolarized 129Xe that has been…

Singulett‐Kontrast‐Magnetresonanztomographie: Freisetzung der Hyperpolarisation durch den Metabolismus**

Singlet‐Contrast Magnetic Resonance Imaging: Unlocking Hyperpolarization with Metabolism

Abstract Hyperpolarization‐enhanced magnetic resonance imaging can be used to study biomolecular processes in the body, but typically requires nuclei such as 13C, 15N, or 129Xe due to their long spin‐polarization lifetimes and the absence of a proton‐background signal from water and fat in the images. Here we present a novel type of 1H imaging, in which hyperpolarized spin order is locked in a nonmagnetic long‐lived correlated (singlet) state, and is only liberated for imaging by a specific biochemical reaction. In this work we produce hyperpolarized fumarate via chemical reaction of a precursor molecule with para‐enriched hydrogen gas, and the proton singlet order in fumarate is released a…

NMR Hyperpolarization of Established PET Tracers

Heparin–polynitroxides: Synthesis and preliminary evaluation as cardiovascular EPR/MR imaging probes and extracellular space-targeted antioxidants

We report here the synthesis of heparin-polynitroxide derivatives (HPNs) in which nitroxide moieties are linked either to uronic acid or glycosamine residues of the heparin macromolecule. HPNs have low anticoagulant activity, possess superoxide scavenging properties, bind to the vascular endothelium/extra-cellular matrix and can be detected by EPR and MRI techniques. As the vascular wall-targeted redox-active paramagnetic compounds, HPNs may have both diagnostic (molecular MRI) and therapeutic (ecSOD mimics) applications.

Development of MR active contrast agents via Parahydrogen Induced Polarization

Parahydrogen Induced Polarization provides dramatic MR signal enhancement that can be exploited for molecular imaging. This method allows amongst others for Magnetic Resonance Imaging of 13C and 15N, which is usually constrained by the low MR sensitivity of these nuclei. By combining hydrogenation of barbiturates with parahydrogen under special experimental conditions (PASADENA under pressure) with a polarization transfer sequence we demonstrate the transfer of the initial 1H polarization to 13C. The polarization transfer yields a signal increase for 13C of more than 1000. Hence, the role of certain target compounds such as anesthetics like the barbituric acid derivatives could be investiga…

Towards Large-Scale Steady-State Enhanced Nuclear Magnetization with In Situ Detection

Signal Amplification By Reversible Exchange (SABRE) boosts NMR signals of various nuclei enabling new applications spanning from magnetic resonance imaging to analytical chemistry and fundamental physics. SABRE is especially well positioned for continuous generation of enhanced magnetization on a large scale, however, several challenges need to be addressed for accomplishing this goal. Specifically, SABRE requires (i) a specialized catalyst capable of reversible H2 activation and (ii) physical transfer of the sample from the point of magnetization generation to the point of detection (e.g., a high-field or a benchtop NMR spectrometer). Moreover, (iii) continuous parahydrogen bubbling accele…

Mechanistic Understanding of Food Effects: Water Diffusivity in Gastrointestinal Tract Is an Important Parameter for the Prediction of Disintegration of Solid Oral Dosage Forms

Much interest has been expressed in this work on the role of water diffusivity in the release media as a new parameter for predicting drug release. NMR was used to measure water diffusivity in different media varying in their osmolality and viscosity. Water self-diffusion coefficients in sucrose, sodium chloride, and polymeric hydroxypropyl methylcellulose (HPMC) solutions were correlated with water uptake, disintegration, and drug release rates from trospium chloride immediate release tablets. The water diffusivity in sucrose solutions was significantly reduced compared to polymeric HPMC and molecular sodium chloride solutions. Water diffusivity was found to be a function of sucrose concen…

Quantitative contrast-enhanced myocardial perfusion magnetic resonance imaging: Simulation of bolus dispersion in constricted vessels

Quantification of myocardial blood flow (MBF) by means of T 1 -weighted first-pass magnetic resonance imaging(MRI) requires knowledge of the arterial input function (AIF), which is usually estimated from the left ventricle (LV). Dispersion of the contrast agent bolus may occur between the LV and the tissue of interest, which leads to systematic underestimation of the MBF. The aim of this study was to simulate the dispersion along a simplified coronary artery with different stenoses. To analyze the dispersion in vessels with typical dimensions of coronary arteries, simulations were performed using the computational fluid dynamics approach. Simulations were accomplished on straight vessels wi…

Proton magnetic resonance imaging with para-hydrogen induced polarization.

A major challenge in imaging is the detection of small amounts of molecules of interest. In the case of magnetic resonance imaging (MRI) their signals are typically concealed by the large background signal of e.g. the body. This problem can be tackled by hyperpolarization which increases the NMR signals up to several orders of magnitude. However, this strategy is limited for (1)H, the most widely used nucleus in NMR and MRI, because the enormous number of protons in the body screens the small amount of hyperpolarized ones. Here, we describe a method giving rise to high (1)H MRI contrast for hyperpolarized molecules against a large background signal. The contrast is based on the J-coupling i…

Rapid hyperpolarization and purification of the metabolite fumarate in aqueous solution

Significance Magnetic resonance imaging is hindered by inherently low sensitivity, which limits the method for the most part to observing water molecules in the body. Hyperpolarized molecules exhibit strongly enhanced MRI signals which opens the door for imaging low-concentration species in vivo. Biomolecules can be hyperpolarized and injected into a patient allowing for metabolism to be tracked in real time, greatly expanding the information available to the radiologist. Parahydrogen-induced polarization (PHIP) is a hyperpolarization method renowned for its low cost and accessibility, but is generally limited by low polarization levels, modest molecular concentrations, and contamination by…

Development of a Polarizer and Biocompatible Polarizing Agents for Use in Dynamic Nuclear Polarization DNP-Enhanced NMR and MRI

The application of 13C (or other low γ nuclei) NMR spectroscopy and imaging for clinical diagnosis has been constrained by the extremely long imaging and spectroscopy acquisition times that are required to obtain high SNR under physiological conditions (low natural abundance of 13C, low concentration of 13C-compounds, physiological temperature etc.). However, this obstacle could be overcome by in vitro hyperpolarization of a 13C-containing molecule with long spin lattice relaxation time via dynamic nuclear polarization (DNP) and subsequent injection into the animal or patient of investigation [1, 2]. DNP is achieved by resonant excitation of electron spins of radicals (electron paramagnetic…

Towards large‐scale steady‐state enhanced nuclear magnetization with in situ detection

Magnetic resonance in chemistry 59(12), 1208 - 1215 (2021). doi:10.1002/mrc.5161

Spin‐Labeled Heparins as Polarizing Agents for Dynamic Nuclear Polarization

A potentially biocompatible class of spin-labeled macromolecules, spin-labeled (SL) heparins, and their use as nuclear magnetic resonance (NMR) signal enhancers are introduced. The signal enhancement is achieved through Overhauser-type dynamic nuclear polarization (DNP). All presented SL-heparins show high 1 H DNP enhancement factors up to E=-110, which validates that effectively more than one hyperfine line can be saturated even for spin-labeled polarizing agents. The parameters for the Overhauser-type DNP are determined and discussed. A striking result is that for spin-labeled heparins, the off-resonant electron paramagnetic resonance (EPR) hyperfine lines contribute a non-negligible part…

Magnetic resonance imaging of (1)H long lived states derived from parahydrogen induced polarization in a clinical system.

Hyperpolarization is a powerful tool to overcome the low sensitivity of nuclear magnetic resonance (NMR). However, applications are limited due to the short lifetime of this non equilibrium spin state caused by relaxation processes. This issue can be addressed by storing hyperpolarization in slowly decaying singlet spin states which was so far mostly demonstrated for non-proton spin pairs, e.g. 13C-13C. Protons hyperpolarized by parahydrogen induced polarization (PHIP) in symmetrical molecules, are very well suited for this strategy because they naturally exhibit a long-lived singlet state. The conversion of the NMR silent singlet spin state to observable magnetization can be achieved by ma…