While many drugs and metabolites contain nitrogen, harnessing their diagnostic 15N NMR signature for their characterization is underutilized because of inherent detection difficulties. Here, we demonstrate how precise ultralow field signal amplification by reversible exchange (±0.2 mG) in conjunction parahydrogen and an iridium precatalyst of the form IrCl(COD)(NHC) with the coligand d9-benzylamine allows the naturally abundant 15N NMR signatures of pyridine, pyrazine, metronidazole, and acetonitrile to be readily detected at 9.4 T in single NMR observations through >50% 15N polarization levels. These signals allow for rapid and precise reagent quantification via a response that varies linearly over the 2-70 mM concentration range.

https://pubs.acs.org/doi/pdf/10.1021/acs.jpcb.0c02583

Remarkable Levels of 15N Polarization Delivered through SABRE into Unlabeled Pyridine, Pyrazine, or Metronidazole Enable Single Scan NMR Quantification at the mM Level.

Personalized medicine is probably the most promising areas being developed in modern medicine. This approach attempts to optimize the therapies and the patient care based on the individual patient characteristics. Its success highly depends on the way in which the characterization of the disease and its evolution, the patient’s classification, its follow-up and the treatment could be optimized. Thus, personalized medicine must combine innovative tools to measure, integrate and model data. Towards this goal, clinical metabolomics appears as ideally suited to obtain relevant information. Indeed, the metabolomics signature brings crucial insight to stratify patients according to their responses to a pathology and/or a treatment, to provide prognostic and diagnostic biomarkers, and to improve therapeutic outcomes. However, the translation of metabolomics from laboratory studies to clinical practice remains a subsequent challenge. Nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) are the two key platforms for the measurement of the metabolome. NMR has several advantages and features that are essential in clinical metabolomics. Indeed, NMR spectroscopy is inherently very robust, reproducible, unbiased, quantitative, informative at the structural molecular level, requires little sample preparation and reduced data processing. NMR is also well adapted to the measurement of large cohorts, to multi-sites and to longitudinal studies. This review focus on the potential of NMR in the context of clinical metabolomics and personalized medicine. Starting with the current status of NMR-based metabolomics at the clinical level and highlighting its strengths, weaknesses and challenges, this article also explores how, far from the initial “opposition” or “competition”, NMR and MS have been integrated and have demonstrated a great complementarity, in terms of sample classification and biomarker identification. Finally, a perspective discussion provides insight into the current methodological developments that could significantly raise NMR as a more resolutive, sensitive and accessible tool for clinical applications and point-of-care diagnosis. Thanks to these advances, NMR has a strong potential to join the other analytical tools currently used in clinical settings.

/pdf/nuclear-magnetic-resonance-spectroscopy-in-clinical-3l308n0fjr.pdf

Nuclear Magnetic Resonance Spectroscopy in Clinical Metabolomics and Personalized Medicine: Current Challenges and Perspectives.

Magnetic resonance techniques are successfully utilized in a broad range of scientific disciplines and in various practical applications, with medical magnetic resonance imaging being the most widely known example. Currently, both fundamental and applied magnetic resonance are enjoying a major boost owing to the rapidly developing field of spin hyperpolarization. Hyperpolarization techniques are able to enhance signal intensities in magnetic resonance by several orders of magnitude, and thus to largely overcome its major disadvantage of relatively low sensitivity. This provides new impetus for existing applications of magnetic resonance and opens the gates to exciting new possibilities. In this review, we provide a unified picture of the many methods and techniques that fall under the umbrella term “hyperpolarization” but are currently seldom perceived as integral parts of the same field. Specifically, before delving into the individual techniques, we provide a detailed analysis of the underlying principles of spin hyperpolarization. We attempt to uncover and classify the origins of hyperpolarization, to establish its sources and the specific mechanisms that enable the flow of polarization from a source to the target spins. We then give a more detailed analysis of individual hyperpolarization techniques: the mechanisms by which they work, fundamental and technical requirements, characteristic applications, unresolved issues, and possible future directions. We are seeing a continuous growth of activity in the field of spin hyperpolarization, and we expect the field to flourish as new and improved hyperpolarization techniques are implemented. Some key areas for development are in prolonging polarization lifetimes, making hyperpolarization techniques more generally applicable to chemical/biological systems, reducing the technical and equipment requirements, and creating more efficient excitation and detection schemes. We hope this review will facilitate the sharing of knowledge between subfields within the broad topic of hyperpolarization, to help overcome existing challenges in magnetic resonance and enable novel applications.

Spin Hyperpolarization in Modern Magnetic Resonance

The scope of non-hydrogenative parahydrogen hyperpolarization (nhPHIP) techniques has been expanding over the last years, with the continuous addition of important classes of substrates. For example, pyruvate can now be hyperpolarized using the Signal Amplification By Reversible Exchange (SABRE) technique, offering a fast, efficient and low-cost PHIP alternative to Dynamic Nuclear Polarization for metabolic imaging studies. Still, important biomolecules such as amino acids have so far resisted PHIP, unless properly functionalized. Here, we report on an approach to nhPHIP for unmodified α-amino acids that allows their detection and quantification in complex mixtures at sub-micromolar concentrations. This method was tested on human urine, in which natural α-amino acids could be measured after dilution with methanol without any additional sample treatment.

Parahydrogen Hyperpolarization Allows Direct NMR Detection of α-Amino Acids in Complex (Bio)mixtures.

Advances in nano- and microscale NMR spectroscopy using diamond quantum sensors

Parahydrogen induced hyperpolarization provides a tool for NMR metabolomics at nanomolar concentrations.

. Non-hydrogenative para-hydrogen-induced polarization (PHIP) is a fast, efficient and relatively inexpensive approach to enhance nuclear magnetic resonance (NMR) signals of small molecules in solution. The
efficiency of this technique depends on the interplay of NMR relaxation and
kinetic processes, which, at high concentrations, can be characterized by
selective inversion experiments. However, in the case of dilute solutions
this approach is clearly not viable. Here, we present alternative PHIP-based
NMR experiments to determine hydrogen and hydride relaxation parameters as well as the rate constants for para-hydrogen association with and dissociation
from asymmetric PHIP complexes at micromolar concentrations. Access to these
parameters is necessary to understand and improve the PHIP enhancements of
(dilute) substrates present in, for instance, biofluids and natural
extracts.

/pdf/determination-of-hydrogen-exchange-and-relaxation-parameters-45jsyweu58.pdf

Determination of hydrogen exchange and relaxation parameters in PHIP complexes at micromolar concentrations

Understanding and controlling decoherence in open quantum systems is of fundamental interest in science, while achieving long coherence times is critical for quantum information processing. Although great progress was made for individual, isolated systems, and electron spin resonance (ESR) of single spins with nanoscale resolution has been demonstrated, the construction of complex solid-state quantum devices requires ultimately controlling the environment down to atomic scales, as potentially enabled by scanning probe microscopy with its atomic and molecular characterization and manipulation capabilities. Consequently, the recent implementation of ESR in scanning tunneling microscopy (STM) represents a milestone towards this goal and was quickly followed by the demonstration of coherent oscillations, tunable dipolar and exchange couplings and access to nuclear spins with real-space atomic resolution. Atomic manipulation even fueled the ambition to realize first artificial atomic-scale quantum devices. However, the current-based sensing inherent to this method limits coherence times. Here, we demonstrate pump-probe ESR atomic force microscopy detection of electron spin transitions between non-equilibrium triplet states of individual pentacene molecules. Spectra of these transitions exhibit sub-nanoelectronvolt energy resolution, allowing local discrimination of molecules that only differ in their isotopic configuration. Furthermore, the electron spins can be coherently manipulated over tens of microseconds, likely not limited by the detection method but by the molecular properties. Single-molecule ESR atomic force microscopy can be combined with atomic manipulation and characterization, and thereby paves the way for atomically well-defined quantum components with long coherence times and local quantum-sensing experiments.

Lisanne Sellies

Papers

Parahydrogen induced hyperpolarization provides a tool for NMR metabolomics at nanomolar concentrations.

Parahydrogen Hyperpolarization Allows Direct NMR Detection of α-Amino Acids in Complex (Bio)mixtures.

Determination of hydrogen exchange and relaxation parameters in PHIP complexes at micromolar concentrations

Atomic-scale access to long spin coherence in single molecules with scanning force microscopy