Singlet-Contrast Magnetic Resonance Imaging: Unlocking Hyperpolarization with Metabolism*.

Hyperpolarization-enhanced magnetic resonance imaging can be used to study biomolecular processes in the body, but typically requires nuclei such as 13 C, 15 N, or 129 Xe 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 1 H 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 as antiphase NMR signals by enzymatic conversion to malate in D2 O. Using this model system we show two pulse sequences to rephase the NMR signals for imaging and suppress the background signals from water. The hyperpolarization-enhanced 1 H-imaging modality presented here can allow for hyperpolarized imaging without the need for low-abundance, low-sensitivity heteronuclei.

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 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 (1)H singlet state lifetime of several minutes, the conversion of the NMR silent singlet state to observable magnetization is feasible due to the existence of singlet-triplet level anti-crossings. Here, we demonstrate that scaling the chemical shift Hamiltonian by rf irradiation is sufficient to transform the singlet into an observable triplet state. Moreover, because the application of one long rf pulse is only partially converting the singlet state, we developed a multiconversion sequence consisting of a train of long rf pulses resulting in successive singlet to triplet conversions. This sequence is used to measure the singlet state relaxation time in a simple way at two different magnetic fields. We show that this approach is valid for almost any magnetic field strength and can be performed even in the less homogeneous field of an MRI scanner, allowing for new applications of hyperpolarized NMR and MRI.

High resolution para-hydrogen induced polarization in inhomogeneous magnetic fields.

The application of parahydrogen for the generation of hyperpolarization has increased continuously during the last years. When the chemical reaction is carried out at the same field as the NMR experiment (PASADENA protocol) an antiphase signal is obtained, with a separation of the resonance lines of a few Hz. This imposes a stringent limit to the homogeneity of the magnetic field in order to avoid signal cancellation. In this work we detect the signal arising from hyperpolarized Hexene by means of a CPMG pulse train. After Fourier transformation the obtained J-spectra not only presents an enhanced spectral resolution but also avoids partial peak cancellation.

Level anti-crossings in ParaHydrogen Induced Polarization experiments with Cs-symmetric molecules.

Hyperpolarization by means of ParaHydrogen Induced Polarization (PHIP) has found increasing applications since its discovery. However, in the last decade only a few experiments have been reported describing the hydrogenation of symmetric molecules. A general AA'BB' system is studied here. Calculations of the spin dynamics with the density matrix formalism support the experimental findings, providing profound understanding of the experiments in Cs-symmetric molecules. Level anti-crossings between states related to the triplet and the singlet state of one pair of the protons are identified as being responsible for hyperpolarization transfer in a PHIP experiment, when the former p-H(2) protons occupy the sites AA'. The hydrogenation of acetylene dicarboxylic acid dimethylester with parahydrogen is used to illustrate the case. The theoretical treatment applied to this particular reaction explains the signal enhancements in both groups of protons in the spectrum when the sample is placed in the proper magnetic field strength, including the phase inversion of the signal of the methyl group. The treatment described here can be extended to every molecule which can be approximated as an AA'BB' system.

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

A technique for continuous production of solutions containing hyperpolarized (129)Xe 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 (129)Xe 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 (129)Xe contrast agents produced with our dissolution method for lung MRI by imaging hyperpolarized (129)Xe that has been both dissolved in and outgassed from a carrier liquid in a lung phantom, illustrating its potential for the measurement of lung perfusion and ventilation.

Time resolved spectroscopic NMR imaging using hyperpolarized 129Xe.

We have visualized the melting and dissolution processes of xenon (Xe) ice into different solvents using the methods of nuclear magnetic resonance (NMR) spectroscopy, imaging, and time resolved spectroscopic imaging by means of hyperpolarized 129Xe. Starting from the initial condition of a hyperpolarized solid Xe layer frozen on top of an ethanol (ethanol/water) ice block we measured the Xe phase transitions as a function of time and temperature. In the pure ethanol sample, pieces of Xe ice first fall through the viscous ethanol to the bottom of the sample tube and then form a thin layer of liquid Xe/ethanol. The xenon atoms are trapped in this liquid layer up to room temperature and keep their magnetization over a time period of 11 min. In the ethanol/water mixture (80 vol%/20%), most of the polarized Xe liquid first stays on top of the ethanol/water ice block and then starts to penetrate into the pores and cracks of the ethanol/water ice block. In the final stage, nearly all the Xe polarization is in the gas phase above the liquid and trapped inside the pores. NMR spectra of homogeneous samples of pure ethanol containing thermally polarized Xe and the spectroscopic images of the melting process show that very high concentrations of hyperpolarized Xe (about half of the density of liquid Xe) can be stored or delivered in pure ethanol.