An official website of the United States government
Abstract Signal Amplification by Reversible Exchange (SABRE) technique enables nuclear spin hyperpolarization of wide range of compounds using parahydrogen. Here we present the synthetic approach to prepare15N‐labeled [15N]dalfampridine (4‐amino[15N]pyridine) utilized as a drug to reduce the symptoms of multiple sclerosis. The synthesized compound was hyperpolarized using SABRE at microtesla magnetic fields (SABRE‐SHEATH technique) with up to 2.0 %15N polarization. The 7‐hour‐long activation of SABRE pre‐catalyst [Ir(IMes)(COD)Cl] in the presence of [15N]dalfampridine can be remedied by the use of pyridine co‐ligand for catalyst activation while retaining the15N polarization levels of [15N]dalfampridine. The effects of experimental conditions such as polarization transfer magnetic field, temperature, concentration, parahydrogen flow rate and pressure on15N polarization levels of free and equatorial catalyst‐bound [15N]dalfampridine were investigated. Moreover, we studied15N polarization build‐up and decay at magnetic field of less than 0.04 μT as well as15N polarization decay at the Earth's magnetic field and at 1.4 T.
more »
« less
This content will become publicly available on December 1, 2025
Analysis of chemical exchange in iridium N-heterocyclic carbene complexes using heteronuclear parahydrogen-enhanced NMR
Abstract The signal amplification by reversible exchange process (SABRE) enhances NMR signals by unlocking hidden polarization in parahydrogen through interactions with to-be-hyperpolarized substrate molecules when both are transiently bound to an Ir-based organometallic catalyst. Recent efforts focus on optimizing polarization transfer from parahydrogen-derived hydride ligands to the substrate in SABRE. However, this requires quantitative information on ligand exchange rates, which common NMR techniques struggle to provide. Here, we introduce an experimental spin order transfer sequence, with readout occurring at15N nuclei directly interacting with the catalyst. Enhanced15N NMR signals overcome sensitivity challenges, encoding substrate dissociation rates. This methodology enables robust data fitting to ligand exchange models, yielding substrate dissociation rate constants with higher precision than classical 1D and 2D1H NMR approaches. This refinement improves the accuracy of key activation enthalpy ΔH‡and entropy ΔS‡estimates. Furthermore, the higher chemical shift dispersion provided by enhanced15N NMR reveals the kinetics of substrate dissociation for acetonitrile and metronidazole, previously inaccessible via1H NMR due to small chemical shift differences between free and Ir-bound substrates. The presented approach can be successfully applied not only to isotopically enriched substrates but also to compounds with natural abundance of the to-be-hyperpolarized heteronuclei.
more »
« less
- Award ID(s):
- 2404388
- PAR ID:
- 10607899
- Publisher / Repository:
- Nature Portfolio
- Date Published:
- Journal Name:
- Communications Chemistry
- Volume:
- 7
- Issue:
- 1
- ISSN:
- 2399-3669
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE‐SHEATH) is investigated to achieve rapid hyperpolarization of13C1spins of [1‐13C]pyruvate, using parahydrogen as the source of nuclear spin order. Pyruvate exchange with an iridium polarization transfer complex can be modulated via a sensitive interplay between temperature and co‐ligation of DMSO and H2O. Order‐unity13C (>50 %) polarization of catalyst‐bound [1‐13C]pyruvate is achieved in less than 30 s by restricting the chemical exchange of [1‐13C]pyruvate at lower temperatures. On the catalyst bound pyruvate, 39 % polarization is measured using a 1.4 T NMR spectrometer, and extrapolated to >50 % at the end of build‐up in situ. The highest measured polarization of a 30‐mM pyruvate sample, including free and bound pyruvate is 13 % when using 20 mM DMSO and 0.5 M water in CD3OD. Efficient13C polarization is also enabled by favorable relaxation dynamics in sub‐microtesla magnetic fields, as indicated by fast polarization buildup rates compared to theT1spin‐relaxation rates (e. g., ∼0.2 s−1versus ∼0.1 s−1, respectively, for a 6 mM catalyst‐[1‐13C]pyruvate sample). Finally, the catalyst‐bound hyperpolarized [1‐13C]pyruvate can be released rapidly by cycling the temperature and/or by optimizing the amount of water, paving the way to future biomedical applications of hyperpolarized [1‐13C]pyruvate produced via comparatively fast and simple SABRE‐SHEATH‐based approaches.more » « less
-
Abstract Herein, we demonstrate “direct”13C hyperpolarization of13C‐acetate via signal amplification by reversible exchange (SABRE). The standard SABRE homogeneous catalyst [Ir‐IMes; [IrCl(COD)(IMes)], (IMes=1,3‐bis(2,4,6‐trimethylphenyl), imidazole‐2‐ylidene; COD=cyclooctadiene)] was first activated in the presence of an auxiliary substrate (pyridine) in alcohol. Following addition of sodium 1‐13C‐acetate, parahydrogen bubbling within a microtesla magnetic field (i.e. under conditions of SABRE in shield enables alignment transfer to heteronuclei, SABRE‐SHEATH) resulted in positive enhancements of up to ≈100‐fold in the13C NMR signal compared to thermal equilibrium at 9.4 T. The present results are consistent with a mechanism of “direct” transfer of spin order from parahydrogen to13C spins of acetate weakly bound to the catalyst, under conditions of fast exchange with respect to the13C acetate resonance, but we find that relaxation dynamics at microtesla fields alter the optimal matching from the traditional SABRE‐SHEATH picture. Further development of this approach could lead to new ways to rapidly, cheaply, and simply hyperpolarize a broad range of substrates (e.g. metabolites with carboxyl groups) for various applications, including biomedical NMR and MRI of cellular and in vivo metabolism.more » « less
-
Abstract Nimorazole belongs to the imidazole‐based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [15N3]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next‐generation MRI‐LINAC systems. Herein, we report the first steps to create long‐lasting (for tens of minutes) hyperpolarized state on three15N sites of [15N3]nimorazole with T1of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000‐fold at 1.4 T (corresponding toP15Nof 3.2 %) by15N−15N spin‐relayed SABRE‐SHEATH hyperpolarization technique, relying on simultaneous exchange of [15N3]nimorazole and parahydrogen on polarization transfer Ir‐IMes catalyst. The presented results pave the way to efficient spin‐relayed SABRE‐SHEATH hyperpolarization of a wide range of imidazole‐based antibiotics and chemotherapeutics.more » « less
-
Abstract NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This enormous sensitivity gain enables new applications ranging from studies of small molecules by using high‐resolution NMR spectroscopy to real‐time metabolic imagingin vivo. Several hyperpolarization techniques exist for hyperpolarization of a large repertoire of nuclear spins, although the13C and15N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their longT1allows hyperpolarized states to be retained for up to tens of minutes. Signal amplification by reversible exchange (SABRE) is a low‐cost and ultrafast hyperpolarization technique that has been shown to be versatile for the hyperpolarization of15N nuclei. Although large sensitivity gains are enabled by hyperpolarization,15N natural abundance is only ∼0.4 %, so isotopic labeling of the molecules to be hyperpolarized is required in order to take full advantage of the hyperpolarized state. Herein, we describe selected advances in the preparation of15N‐labeled compounds with the primary emphasis on using these compounds for SABRE polarization in microtesla magnetic fields through spontaneous polarization transfer from parahydrogen. Also, these principles can certainly be applied for hyperpolarization of these emerging contrast agents using dynamic nuclear polarization and other techniques.more » « less
