Jan-Bernd Hövener

Toward Biocompatible Nuclear Hyperpolarization Using Signal Amplification by Reversible Exchange: Quantitative in Situ Spectroscopy and High-Field Imaging

Signal amplification by reversible exchange (SABRE) of a substrate and parahydrogen at a catalytic center promises to overcome the inherent insensitivity of magnetic resonance. In order to apply the new approach to biomedical applications, there is a need to develop experimental equipment, in situ quantification methods, and a biocompatible solvent. We present results detailing a low-field SABRE polarizer which provides well-controlled experimental conditions, defined spins manipulations, and which allows in situ detection of thermally polarized and hyperpolarized samples. We introduce a method for absolute quantification of hyperpolarization yield in situ by means of a thermally polarized reference. A maximum signal-to-noise ratio of ∼103 for 148 μmol of substance, a signal enhancement of 106 with respect to polarization transfer field of SABRE, or an absolute 1H-polarization level of ≈10–2 is achieved. In an important step toward biomedical application, we demonstrate 1H in situ NMR as well as 1H and 13C high-field MRI using hyperpolarized pyridine (d3) and 13C nicotinamide in pure and 11% ethanol in aqueous solution. Further increase of hyperpolarization yield, implications of in situ detection, and in vivo application are discussed.

A hyperpolarized equilibrium for magnetic resonance.

Nuclear magnetic resonance spectroscopy and imaging (MRI) play an indispensable role in science and healthcare but use only a tiny fraction of their potential. No more than ≈10 p.p.m. of all 1H nuclei are effectively detected in a 3-Tesla clinical MRI system. Thus, a vast array of new applications lays dormant, awaiting improved sensitivity. Here we demonstrate the continuous polarization of small molecules in solution to a level that cannot be achieved in a viable magnet. The magnetization does not decay and is effectively reinitialized within seconds after being measured. This effect depends on the long-lived, entangled spin-order of parahydrogen and an exchange reaction in a low magnetic field of 10−3 Tesla. We demonstrate the potential of this method by fast MRI and envision the catalysis of new applications such as cancer screening or indeed low-field MRI for routine use and remote application.

A continuous-flow, high-throughput, high-pressure parahydrogen converter for hyperpolarization in a clinical setting.

Pure parahydrogen (pH2) is the prerequisite for optimal pH2‐based hyperpolarization experiments, promising approaches to access the hidden orders of magnitude of MR signals. pH2 production on‐site in medical research centers is vital for the proliferation of these technologies in the life sciences. However, previously suggested designs do not meet our requirements for safety or production performance (flow rate, pressure or enrichment). In this article, we present the safety concept, design and installation of a pH2 converter, operated in a clinical setting. The apparatus produces a continuous flow of four standard liters per minute of ≈98% enriched pH2 at a pressure maximum of 50 bar. The entire production cycle, including cleaning and cooling to 25 K, takes less than 5 h, only ≈45 min of which are required for actual pH2 conversion. A fast and simple quantification procedure is described. The lifetimes of pH2 in a glass vial and aluminum storage cylinder are measured to be T1C(glass vial) = 822 ± 29 min and T1C(Al cylinder) = 129 ± 36 days, thus providing sufficiently long storage intervals and allowing the application of pH2 on demand. A dependence of line width on pH2 enrichment is observed. As examples, 1H hyperpolarization of pyridine and 13C hyperpolarization of hydroxyethylpropionate are presented. Copyright

Dental MRI: Imaging of soft and solid components without ionizing radiation

To evaluate the ability of conventional and ultra‐short or zero echo time MRI for imaging of soft and solid dental components in and ex vivo.

On the spin order transfer from parahydrogen to another nucleus

The hyperpolarization of nuclear spins holds great potential e.g. for biomedical research. Strong signal enhancements have been demonstrated e.g. by transforming the spin order of parahydrogen (pH(2)) to net polarization of a third nucleus (e.g. (13)C) by means of a spin-order-transfer (SOT) sequence. The polarization achieved is vitally dependent on the sequence intervals, which are a function of the J-coupling constants of the molecule to be polarized. How to derive the SOT sequence intervals, the actual values for molecules as well as the (theoretical) polarization yield and robustness, however, are not fully described. In this paper, (a) we provide the methods to obtain the SOT intervals for a given set of J-coupling constants (i.e. of a new hyperpolarization agent); (b) exemplify these methods on molecules from literature, providing the hitherto missing intervals and simulated polarization yield; and (c) assess the robustness of the sequences towards B(1) and J-coupling errors. Close to unity polarization is obtained for all molecules and sequences. Furthermore, the loss of polarization caused by erroneous B(1) and J-coupling constants is reduced by choosing the channel and phase of some pulses in the SOT sequences appropriately.

Whole-body MRI-based fat quantification: a comparison to air displacement plethysmography.

To demonstrate the feasibility of an algorithm for MRI whole‐body quantification of internal and subcutaneous fat and quantitative comparison of total adipose tissue to air displacement plethysmography (ADP).

Continuous Re‐hyperpolarization of Nuclear Spins Using Parahydrogen: Theory and Experiment

The continuous re-hyperpolarization of nuclear spins in the liquid state by means of parahydrogen (para-H2) and chemical exchange at low magnetic fields was recently discovered and offers intriguing perspectives for many varieties of magnetic resonance. In this contribution, we provide a theoretical assessment of this effect and compare the results to experimental data. A distinct distribution of polarization is found, which shares some features with experimental data and, interestingly, does not directly correspond to the loss of the singlet order of para-H2. We derived expressions for the magnetic field and para-H2-substrate interaction time, for which the polarization transfer is maximal. This work sheds light onto the effect of continuous hyperpolarization and elucidates the underlying mechanism, which may facilitate the development of an optimized catalyst. As an application, continuous hyperpolarization may enable highly sensitive nuclear magnetic resonance at very low magnetic fields, for example, for the cost-efficient screening of drugs.

Dental MRI using wireless intraoral coils

Currently, the gold standard for dental imaging is projection radiography or cone-beam computed tomography (CBCT). These methods are fast and cost-efficient, but exhibit poor soft tissue contrast and expose the patient to ionizing radiation (X-rays). The need for an alternative imaging modality e.g. for soft tissue management has stimulated a rising interest in dental magnetic resonance imaging (MRI) which provides superior soft tissue contrast. Compared to X-ray imaging, however, so far the spatial resolution of MRI is lower and the scan time is longer. In this contribution, we describe wireless, inductively-coupled intraoral coils whose local sensitivity enables high resolution MRI of dental soft tissue. In comparison to CBCT, a similar image quality with complementary contrast was obtained ex vivo. In-vivo, a voxel size of the order of 250∙250∙500 μm3 was achieved in 4 min only. Compared to dental MRI acquired with clinical equipment, the quality of the images was superior in the sensitive volume of the coils and is expected to improve the planning of interventions and monitoring thereafter. This method may enable a more accurate dental diagnosis and avoid unnecessary interventions, improving patient welfare and bringing MRI a step closer to becoming a radiation-free alternative for dental imaging.

Quantitative description of the SABRE process: rigorous consideration of spin dynamics and chemical exchange

A consistent theoretical description of the spin dynamics and chemical kinetics underlying the SABRE (Signal Amplification By Reversible Exchange) process is proposed and validated experimentally. SABRE is a promising method for Nuclear Magnetic Resonance (NMR) signal enhancement, which exploits the transfer of strong non-thermal spin order from parahydrogen (the H2 molecule in its singlet spin state) to a substrate in a transient organometallic complex. A great advantage of the SABRE method is that the substrate acquires strong nuclear spin polarization without being modified chemically, as it is only transiently bound to the complex. However, for the same reason theoretical treatment of SABRE meets difficulties because of the interplay of the spin dynamics with the association–dissociation reactions of the SABRE complex. Here we propose a quantitative model, which takes into account both the spin evolution in the SABRE complex and the substrate exchange between the free and bound forms. The model allows for the calculation of the substrate spin polarization dependency on various parameters, such as the external magnetic field strength and complex association–dissocation rates, and enables the simulation of experimental data for the SABRE time dependence. This investigation opens new insights into the SABRE process and can be generalized to treat more complex cases, such as SABRE facilitated by NMR pulses.

Fast volumetric spatial-spectral MR imaging of hyperpolarized 13C-labeled compounds using multiple echo 3D bSSFP.

PURPOSE The goal of this work was to develop a fast 3D chemical shift imaging technique for the noninvasive measurement of hyperpolarized (13)C-labeled substrates and metabolic products at low concentration. MATERIALS AND METHODS Multiple echo 3D balanced steady state magnetic resonance imaging (ME-3DbSSFP) was performed in vitro on a syringe containing hyperpolarized [1,3,3-2H3; 1-(13)C]2-hydroxyethylpropionate (HEP) adjacent to a (13)C-enriched acetate phantom, and in vivo on a rat before and after intravenous injection of hyperpolarized HEP at 1.5 T. Chemical shift images of the hyperpolarized HEP were derived from the multiple echo data by Fourier transformation along the echoes on a voxel by voxel basis for each slice of the 3D data set. RESULTS ME-3DbSSFP imaging was able to provide chemical shift images of hyperpolarized HEP in vitro, and in a rat with isotropic 7-mm spatial resolution, 93 Hz spectral resolution and 16-s temporal resolution for a period greater than 45 s. CONCLUSION Multiple echo 3D bSSFP imaging can provide chemical shift images of hyperpolarized (13)C-labeled compounds in vivo with relatively high spatial resolution and moderate spectral resolution. The increased signal-to-noise ratio of this 3D technique will enable the detection of hyperpolarized (13)C-labeled metabolites at lower concentrations as compared to a 2D technique.