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Nuclear spin hyperpolarization enables real-time observation of metabolism and intermolecular interactions in vivo. 1-13C-Pyruvate is the leading hyperpolarized tracer currently under evaluation in several clinical trials as a promising molecular imaging agent. Still, the quest for a simple, fast, and efficient hyperpolarization technique is ongoing. Here, we describe that continuous, weak irradiation in the audio-frequency range of the 13C spin at 121 {\mu}T magnetic field (\sim twiceEarth\apos s field) enables spin order transfer from parahydrogen to 13C magnetization of 1-13C-pyruvate. These so-called LIGHT-SABRE pulses couple nuclear spin states of parahydrogen and pyruvate via the J-coupling network of reversibly exchanging Ir-complexes. Using \sim 100% parahydrogen at ambient pressure, we polarized 51 mM of 1-13C-pyruvate in the presence of 5.1 mM Ir-complex continuously and repeatedly to a polarization of 1.1% averaged over free and catalyst-bound pyruvate. The experiments were conducted at -8{\deg}C), where almost exclusively bound pyruvate was observed, corresponding to an estimated 11% polarization on bound pyruvate. The obtained hyperpolarization levels closely match those obtained via SABRE-SHEATH under otherwise identical conditions. The creation of three different types of spin orders was observed: transverse 13C magnetization along the applied magnetic field, 13C z-magnetization along the main field B_0, and 13C-1H zz-spin-order. With a superconducting quantum interference device (SQUID) for detection, we found that the generated spin orders result from tiny 1H-13C J-coupling interactions, which are not visible even with our narrow linewidth below 0.3 Hz.

It is well known that the association of parahydrogen (pH2) with an unsaturated molecule or a transient metalorganic complex can enhance the intensity of NMR signals; the effect is known as parahydrogen-induced polarization (PHIP). During the last decades, numerous methods were proposed for converting pH2-derived nuclear spin order to the observable magnetization of pro-tons or other nuclei of interest, usually 13C or 15N. Here, we analyze the constraints imposed by the topological symmetry of the spin systems on the amplitude of transferred polarization. In asymmetric systems, heteronuclei can be polarized to 100%. However, the amplitude drops to 75% in A2BX systems and further to 50% in A3B2X systems. The latter case is of primary importance for biological applications of PHIP using sidearm hydrogenation (PHIP-SAH). If the polarization is transferred to the same type of nuclei, i.e. 1H, symmetry constraints impose significant boundaries on the spin-order distribution. For AB, A2B, A3B, A2B2, AA'(AA') systems, the maxi-mum average polarization for each spin is 100%, 50%, 33.3%, 25%, and 0, respectively, when A and B (or A') came from pH2 We also discuss the effect of dipole-dipole induced pH2 spin-order distribution in heterogeneous catalysis or nematic liquid crystals. Practical examples from the literature illustrate our theoretical analysis., Comment: 25 pages, 6 figures, appendix A and B

We describe a new method for pulsed spin order transfer (SOT) of parahydrogen induced polarization (PHIP) that enables close to 100 % polarization in incompletely 2H-labeled molecules by exciting only the desired protons in a frequency-selective manner. While a selective pulse (SP) on 1H at the beginning of pulsed SOT had been considered before, using SPs during the SOT suppresses undesired indirect spin-spin interactions. As a result, we achieved a more robust SOT for the SP variants of the phINEPT+ sequence that we refer to as phSPINEPT+. Thereby, for the first time, we report a sequence that is effective for all weakly coupled spin systems. Our simulations show that the method converts close to 100 % of the parahydrogen-derived spin order into 13C hyperpolarization in weakly coupled three-spin systems and partially or fully 2H-labeled molecules if relaxation is neglected. Experimentally we demonstrate high hyperpolarization of 13C with 15.8 % for 1-13C-hydroxyethyl propionate-d3 and 12.6 % for 1-13C-ethyl acetate-d6, which corresponds to ~47 % and ~38 % if the enrichment of parahydrogen had been 100 %. Even in non-2H-labeled molecules, a remarkable 13C polarization is achieved, e.g. up to 20 % were simulated for 100 % pH2, and 1.25 % were obtained experimentally for 1-13C-ethyl pyruvate and 50 % pH2, which can be further improved by faster hydrogenation. As a result, full deuterium labeling may no longer be required e.g., when new PHIP agents are investigated, the synthesis of fully deuterated molecules is too complex, or when a kinetic isotope effect regarding the metabolic conversion rate of an agent is to be avoided. Using SPs during SOT seems very promising and may be extended to other sequences in the context of PHIP and be-yond to make them less prone to experimental imperfections or real molecular environments., Comment: 7 pages, 3 figures and supporting materials

Parahydrogen (pH2) is a convenient and cost efficient source for magnetic resonance signal enhancement. 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 15N molecules. Here, we analyzed a variant of SABRE, consisting of an outer magnetic field alternating between a low field of ~1 \muT, where a polarization transfer takes place, and a higher field >50 \muT (alt-SABRE). We found effects of both of these fields on amplitude and the 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 i.e. some substrates. 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 \muT. The latter should be taken into consideration for an efficient alt-SABRE.

The sensitivity of NMR and MRI can be boosted via hyperpolarization of nuclear spins. However, current methods are costly, polarization is relatively low, or applicability is limited. Here, we report a new hyperpolarization method combining the low-cost, high polarization of hydrogenative parahydrogen-induced polarization (PHIP) with the flexibility of polarization transfer via proton exchange. The new method can be used to polarize various molecules, including alcohols, water, lactate, and pyruvate. On average, only $\approx$3 mM of a hyperpolarized transfer agent was sufficient to significantly enhance the signal of $\approx$100 mM of target molecules via proton exchange. Thus, hydrogenative parahydrogen-induced hyperpolarization with proton exchange (PHIP-X) provides a new avenue for NMR applications beyond the limits imposed by thermal polarization.

Magnetic resonance spectroscopy (MRS) allows the analysis of biochemical processes non invasively and in vivo. Still, its application in clinical diagnostics is rare. Routine MRS is limited to spatial, chemical and temporal resolutions of cubic centimetres, mM and minutes. In fact, the signal of many metabolites is strong enough for detection, but the resonances significantly overlap, exacerbating identification and quantification. In addition, the signals of water and lipids are much stronger and dominate the entire spectrum. To suppress the background and isolate selected signals, usually, relaxation times, J-coupling and chemical shifts are used. Here, we propose methods to isolate the signals of selected molecular groups within endogenous metabolites by using long-lived spin states (LLS). We exemplify the method by preparing the LLSs of coupled protons in the endogenous molecules N-acetyl-L-aspartic acid (NAA). First, we store polarization in long-lived, double spin states and then apply saturation pulses and double quantum filters to suppress background signals. We show that LLS can be used to selectively prepare and measure the signals of chosen metabolites or drugs in the presence of water, inhomogeneous field and highly concentrated fatty solutions. The pH measurement presented here is one of the possible applications., Comment: 15 pages, 5 figures and supporting materials

Nuclear Magnetic Resonance (NMR) is an intriguing quantum-mechanical effect that is used for daily life medical diagnostics and chemical analysis alike. Numerous advancements have contributed to the success of the technique, including hyperpolarized contrast agents that enables real-time imaging of metabolism in vivo. In physics, hyperpolarization has enabled an NMR RASER using a custom low-field setup and high-Q coils only recently. Expanding on this discovery, we report the finding of a RASER emitting 1H NMR signal continuously for more than 10 min at a high frequency of 600 MHz. Full chemical shift resolution is maintained and a linewidth of 2 ppb was achieved. A new simulation of a RASER effect in a coupled two spin-1/2 system was implemented and reproduced experimental findings. The effect was found using standard equipment only; no dedicated setup is necessary, making the NMR RASER accessible to a wide group of researchers., Comment: maing text 7 pages and 3 figures, appendix 15 pages and 8 figures

We propose a robust and highly efficient NMR technique to create singlet spin order from longitudinal spin magnetization in coupled spin-1/2 pairs and to perform backward conversion (singlet order)$\to$magnetization. In this method we exploit adiabatic switching of an RF-field in order to drive transitions between the singlet state and the $T_\pm$ triplet states of a spin pair under study. We demonstrate that the method works perfectly for both strongly and weakly coupled spin pairs, providing a conversion efficiency between the singlet spin order and magnetization, which is equal to the theoretical maximum. We anticipate that the proposed technique is useful for generating long-lived singlet order, for preserving spin hyperpolarization and for assessing singlet spin order in nearly equivalent spin pairs in specially designed molecules and in low-field NMR studies., Comment: 21 pages, 11 figures