Signal Amplification by Reversible Exchange (SABRE) is a fast and convenient NMR hyperpolarization method that uses cheap and readily available para-hydrogen as a hyperpolarization source. SABRE can hyperpolarize protons and heteronuclei. Here we focus on the heteronuclear variant introduced as SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) and nitrogen-15 targets in particular. We show that 15N-SABRE works more efficiently and on a wider range of substrates than 1H-SABRE, greatly generalizing the SABRE approach. In addition, we show that nitrogen-15 offers significantly extended T1 times of up to 12 minutes. Long T1 times enable higher hyperpolarization levels but also hold the promise of hyperpolarized molecular imaging for several tens of minutes. Detailed characterization and optimization are presented, leading to nitrogen-15 polarization levels in excess of 10% on several compounds.

Parahydrogen is an inexpensive and readily available source of hyperpolarization used to enhance magnetic resonance signals by up to 4 orders of magnitude above thermal signals obtained at ~10 T. A significant challenge for applications is fast signal decay after hyperpolarization. Here, we use parahydrogen based polarization transfer catalysis at micro-Tesla fields (first introduced as SABRE-SHEATH) to hyperpolarize 13C2 spin pairs and find decay time constants of 12 s for magnetization at 0.3 mT, which are extended to 2 minutes at that same field, when long-lived singlet states are hyperpolarized instead. Enhancements over thermal at 8.5 T are between 30 and 170 fold (0.02% to 0.12% polarization). We control the spin dynamics of polarization transfer by choice of μT field allowing for deliberate hyperpolarization of either magnetization or long-lived singlet states. Density functional theory (DFT) calculations and experimental evidence identify two energetically close mechanisms for polarization transfer: First, a model that involves direct binding of the 13C2 pair to the polarization transfer catalyst (PTC), and second, a model transferring polarization through auxiliary protons in substrates.

Nuclear spin hyperpolarization techniques are revolutionizing the field of C molecular MRI. While dissolution dynamic nuclear polarization (d-DNP) is currently the leading technique, it is generally slow (requiring ≈1 h) and costly (≈$USD10 ). As a consequence of carbon's central place in biochemistry, tremendous progress using C d-DNP bioimaging has been demonstrated to date including a number of clinical trials. Despite numerous attempts to develop alternatives to d-DNP, the competing methods have faced significant translational challenges. Efficient hyperpolarization of N, P, and other heteronuclei using signal amplification by reversible exchange (SABRE) has been reported in 2015, but extension of this technique to C has proven to be challenging. Here, we present efficient hyperpolarization of C nuclei using micro-Tesla SABRE. Up to ca. 6700-fold enhancement of nuclear spin polarization at 8.45 T is achieved within seconds, corresponding to P ≈4.4 % using 50 % parahydrogen (P >14 % would be feasible using more potent ≈100 % parahydrogen). Importantly, the C polarization achieved via SABRE strongly depends not only upon spin-lattice relaxation, but also upon the presence of N (I=1/2) versus quadrupolar N (I=1) spins in the site binding the hexacoordinate Ir atom of the catalytic complex. We show that different C nuclei in the test molecular frameworks-pyridine and acetonitrile-can be hyperpolarized, including C sites up to five chemical bonds away from the exchangeable hydrides. The presented approach is highly scalable and can be applied to a rapidly growing number of biomolecules amendable to micro-Tesla SABRE.

Signal Amplification by Reversible-Exchange (SABRE) is a method of hyperpolarizing substrates by polarization transfer from para-hydrogen without hydrogenation. Here, we demonstrate that this method can be applied to hyperpolarize small amounts of all proteinogenic amino acids and some chosen peptides down to the nanomole regime and can be detected in a single scan in low-magnetic fields down to 0.25 mT (10 kHz proton frequency). An outstanding feature is that depending on the chemical state of the used catalyst and the investigated amino acid or peptide, hyperpolarized hydrogen-deuterium gas is formed, which was detected with (1)H and (2)H NMR spectroscopy at low magnetic fields of B(0) = 3.9 mT (166 kHz proton frequency) and 3.2 mT (20 kHz deuterium frequency).

Signal Amplification By Reversible Exchange (SABRE) is an inexpensive, fast, and even continuous hyperpolarization technique that uses para-hydrogen as hyperpolarization source. However, current SABRE faces a number of stumbling blocks for translation to biochemical and clinical settings. Difficulties include inefficient polarization in in water, relatively short lived 1H-polarization, and relatively limited substrate scope. Here we use a water soluble polarization transfer catalyst to hyperpolarize nitrogen-15 in a variety of molecules with SABRE-SHEATH (SABRE in Shield Enables Alignment Transfer to Heteronuclei). This strategy works in pure H2O or D2O solutions, on substrates that could not be hyperpolarized in traditional 1H-SABRE experiments, and we record 15N T1 relaxation times of up to 2 min.

Diazirines are an attractive class of potential molecular tags for magnetic resonance imaging owing to their biocompatibility and ease of incorporation into a large variety of molecules. As recently reported, N -diazirine can be hyperpolarized by the SABRE-SHEATH method, sustaining both singlet and magnetization states, thus offering a path to long-lived polarization storage. Herein, we show the generality of this approach by illustrating that the diazirine tag alone is sufficient for achieving excellent signal enhancements with long-lasting polarization. Our investigations reveal the critical role of Lewis basic additives, including water, on achieving SABRE-promoted hyperpolarization. The application of this strategy to a N -diazirine-containing choline derivative demonstrates the potential of N -diazirines as molecular imaging tags for biomedical applications.

Signal amplification by reversible exchange (SABRE) is an efficient method to hyperpolarize spin-1/2 nuclei and affords signals that are orders of magnitude larger than those obtained by thermal spin polarization. Direct polarization transfer to heteronuclei such as 13C or 15N has been optimized at static microTesla fields or using coherence transfer at high field, and relies on steady state exchange with the polarization transfer catalyst dictated by chemical kinetics. Here we demonstrate that pulsing the excitation field induces complex coherent polarization transfer dynamics, but in fact pulsing with a roughly 1% duty cycle on resonance produces more magnetization than constantly being on resonance. We develop a Monte Carlo simulation approach to unravel the coherent polarization dynamics, show that existing SABRE approaches are quite inefficient in use of para-hydrogen order, and present improved sequences for efficient hyperpolarization.

A one-pot metal-free conversion of unprotected amino acids to terminal diazirines has been developed using phenyliodonium diacetate (PIDA) and ammonia. This PIDAmediated transformation occurs via three consecutive reactions and involves an iodonitrene intermediate. This method is tolerant to most functional groups found on the lateral chain of amino acids, it is operationally simple, and it can be scaled up to provide multigram quantities of diazirine. Interestingly, we also demonstrated that this transformation could be applied to dipeptides without racemization. Furthermore, 14 N 2 and 15 N 2 isotopomers can be obtained, emphasizing a key trans-imination step when using 15 NH 3 . In addition, we report the first experimental observation of 14 N/ 15 N isotopomers directly creating an asymmetric carbon. Finally, the 15 N 2 -diazirine from L-tyrosine was hyperpolarized by a parahydrogen-based method (SABRE-SHEATH), demonstrating the products' utility as hyperpolarized molecular tag.