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Abstract Radio Amplification by Stimulated Emission of Radiation (RASER) is a phenomenon observed during nuclear magnetic resonance (NMR) experiments with strongly negatively polarized systems. This phenomenon may be utilized for the production of very narrow NMR lines, background-free NMR spectroscopy, and excitation-free sensing of chemical transformations. Recently, novel methods of producing RASER by ParaHydrogen-Induced Polarization (PHIP) were introduced. Here, we show that pairwise addition of parahydrogen to various propargylic compounds induces RASER activity of other protons beyond those chemically introduced in the reaction. In high-field PHIP, negative polarization initiating RASER is transferred via intramolecular cross-relaxation. When parahydrogen is added in Earth’s field followed by adiabatic transfer to a high field, RASER activity of other protons is induced via bothJ-couplings and cross-relaxation. This through-bond and through-space induction of RASER holds potential for the ongoing development and expansion of RASER applications and can potentially enhance spectral resolution in two-dimensional NMR spectroscopy techniques. 

Abstract Metronidazole and nimorazole are antibiotics of a nitroimidazole group which also may be potentially utilized as hypoxia radiosensitizers for the treatment of cancerous tumors. Hyperpolarization of¹⁵N nuclei in these compounds using SABRE‐SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei) approach provides dramatic enhancement of detection sensitivity of these analytes using magnetic resonance spectroscopy and imaging. Methanol‐d₄is conventionally employed as a solvent in SABRE hyperpolarization process. Herein, we investigate SABRE‐SHEATH hyperpolarization of isotopically labeled [¹⁵N₃]metronidazole and [¹⁵N₃]nimorazole in nondeuterated methanol and ethanol solvents. Optimization of such hyperpolarization parameters as polarization transfer magnetic field, temperature, parahydrogen flow rate and pressure allowed us to obtain an average¹⁵N polarization of up to 7.2–7.4 % for both substrates. The highest¹⁵N polarizations were observed in methanol‐d₄for [¹⁵N₃]metronidazole and in ethanol for [¹⁵N₃]nimorazole. At a clinically relevant magnetic field of 1.4 T the¹⁵N nuclei of these substrates possess long characteristic hyperpolarization lifetimes (T₁) of ca. 1 to ca. 7 min. This study represents a major step toward SABRE in more biocompatible solvents, such as ethanol, and also paves the way for future utilization of these hyperpolarized nitroimidazoles as molecular contrast agents for MRI visualization of tumors. 

Abstract Real‐time visualization of metabolic processes in vivo provides crucial insights into conditions like cancer and metabolic disorders. Metabolic magnetic resonance imaging (MRI), by amplifying the signal of pyruvate molecules through hyperpolarization, enables non‐invasive monitoring of metabolic fluxes, aiding in understanding disease progression and treatment response. Signal Amplification By Reversible Exchange (SABRE) presents a simpler, cost‐effective alternative to dissolution dynamic nuclear polarization, eliminating the need for expensive equipment and complex procedures. We present the first in vivo demonstration of metabolic sensing in a human pancreatic cancer xenograft model compared to healthy mice. A novel perfluorinated Iridium SABRE catalyst in a fluorinated solvent and methanol blend facilitated this breakthrough with a 1.2‐fold increase in [1‐¹³C]pyruvate SABRE hyperpolarization. The perfluorinated moiety allowed easy separation of the heavy‐metal‐containing catalyst from the hyperpolarized [1‐¹³C]pyruvate target. The perfluorinated catalyst exhibited recyclability, maintaining SABRE‐SHEATH activity through subsequent hyperpolarization cycles with minimal activity loss after the initial two cycles. Remarkably, the catalyst retained activity for at least 10 cycles, with a 3.3‐fold decrease in hyperpolarization potency. This proof‐of‐concept study encourages wider adoption of SABRE hyperpolarized [1‐¹³C]pyruvate MR for studying in vivo metabolism, aiding in diagnosing stages and monitoring treatment responses in cancer and other diseases. 

Abstract It has recently been shown that a bolus of hyperpolarized nuclear spins can yield stimulated emission signals similar in nature to maser signals, potentially enabling new ways of sensing hyperpolarized contrast media, including most notably [1‐¹³C]pyruvate that is under evaluation in over 50 clinical trials for metabolic imaging of cancer. The stimulated NMR signal emissions lasting for minutes do not require radio‐frequency excitation, offering unprecedented advantages compared to conventional MR sensing. However, creating nuclear spin maser emission is challenging in practice due to stringent fundamental requirements, making practical in vivo applications hardly possible using conventional passive MR detectors. Here, we demonstrate the utility of a wireless NMR maser detector, the quality factor of which was enhanced 22‐fold (to 1,670) via parametric pumping. This active‐feedback technique breaks the intrinsic fundamental limit of NMR detector circuit quality factor. We show the use of parametric pumping to reduce the threshold requirement for inducing nuclear spin masing at 300 MHz resonance frequency in a preclinical MRI scanner. Indeed, stimulated emission from hyperpolarized protons was obtained under highly unfavorable conditions of low magnetic field homogeneity (T₂* of 3 ms). Greater gains of the quality factor of the MR detector (up to 1 million) were also demonstrated. 

Abstract We report dissolution Dynamic Nuclear Polarization (d‐DNP) of [¹⁵N₃]metronidazole ([¹⁵N₃]MNZ) for the first time. Metronidazole is a clinically approved antibiotic, which can be potentially employed as a hypoxia‐sensing molecular probe using¹⁵N hyperpolarized (HP) nucleus. The DNP process is very efficient for [¹⁵N₃]MNZ with an exponential build‐up constant of 13.8 min using trityl radical. After dissolution and sample transfer to a nearby 4.7 T Magnetic Resonance Imaging scanner, HP [¹⁵N₃]MNZ lasted remarkably long with T₁values up to 343 s and¹⁵N polarizations up to 6.4 %. A time series of HP [¹⁵N₃]MNZ images was acquired in vitro using a steady state free precession sequence on the¹⁵NO₂peak. The signal lasted over 13 min with notably long T₂of 20.5 s. HP [¹⁵N₃]MNZ was injected in the tail vein of a healthy rat, and dynamic spectroscopy was performed over the rat brain. The in vivo HP¹⁵N signals persisted over 70 s, demonstrating an unprecedented opportunity for in vivo studies. 

Abstract Hyperpolarized orthohydrogen (o‐H₂) is a frequent product of parahydrogen‐based hyperpolarization approaches like signal amplification by reversible exchange (SABRE), where the hyperpolarizedo‐H₂signal is usually absorptive. We describe a novel manifestation of this effect wherein large antiphaseo‐H₂signals are observed, with¹H enhancements up to ≈500‐fold (effective polarizationP_H≈1.6 %). This anomalous effect is attained only when using an intact heterogeneous catalyst constructed using a metal–organic framework (MOF) and is qualitatively independent of substrate nature. This seemingly paradoxical observation is analogous to the “partial negative line” (PNL) effect recently explained in the context of Parahydrogen Induced Polarization (PHIP) by Ivanov and co‐workers. The two‐spin order of theo‐H₂resonance is manifested by a two‐fold higher Rabi frequency, and the lifetime of the antiphase HPo‐H₂resonance is extended by several‐fold. 

Abstract We report on the utility of Radiofrequency Amplification by Stimulated Emission Radiation (RASER) for background‐free proton detection of hyperpolarized biomolecules. We performed hyperpolarization of ≈0.3 M ethyl acetate via pairwise parahydrogen addition to vinyl acetate. A proton NMR signal with signal‐to‐noise ratio exceeding 100 000 was detected without radio‐frequency excitation at the clinically relevant magnetic field of 1.4 T using a standard (non‐cryogenic) inductive detector with quality factor ofQ=68. No proton background signal was observed from protonated solvent (methanol) or other added co‐solvents such as ethanol, water or bovine serum. Moreover, we demonstrate RASER detection without radio‐frequency excitation of a bolus of hyperpolarized contrast agent in biological fluid. Completely background‐free proton detection of hyperpolarized contrast agents in biological media paves the way to new applications in the areas of high‐resolution NMR spectroscopy and in vivo spectroscopy and imaging. 

Abstract The feasibility of Carbon‐13 Radiofrequency (RF) Amplification by Stimulated Emission of Radiation (C‐13 RASER) is demonstrated on a bolus of liquid hyperpolarized ethyl [1‐¹³C]acetate. Hyperpolarized ethyl [1‐¹³C]acetate was prepared via pairwise addition of parahydrogen to vinyl [1‐¹³C]acetate and polarization transfer from nascent parahydrogen‐derived protons to the carbon‐13 nucleus via magnetic field cycling yielding C‐13 nuclear spin polarization of approximately 6 %. RASER signals were detected from samples with concentration ranging from 0.12 to 1 M concentration using a non‐cryogenic 1.4T NMR spectrometer equipped with a radio‐frequency detection coil with a quality factor (Q) of 32 without any modifications. C‐13 RASER signals were observed for several minutes on a single bolus of hyperpolarized substrate to achieve 21 mHz NMR linewidths. The feasibility of creating long‐lasting C‐13 RASER on biomolecular carriers opens a wide range of new opportunities for the rapidly expanding field of C‐13 magnetic resonance hyperpolarization. 

Abstract Metabolic magnetic resonance imaging (MRI) using hyperpolarized (HP) pyruvate is becoming a non‐invasive technique for diagnosing, staging, and monitoring response to treatment in cancer and other diseases. The clinically established method for producing HP pyruvate, dissolution dynamic nuclear polarization, however, is rather complex and slow. Signal Amplification By Reversible Exchange (SABRE) is an ultra‐fast and low‐cost method based on fast chemical exchange. Here, for the first time, we demonstrate not only in vivo utility, but also metabolic MRI with SABRE. We present a novel routine to produce aqueous HP [1‐¹³C]pyruvate‐d₃for injection in 6 minutes. The injected solution was sterile, non‐toxic, pH neutral and contained ≈30 mM [1‐¹³C]pyruvate‐d₃polarized to ≈11 % (residual 250 mM methanol and 20 μM catalyst). It was obtained by rapid solvent evaporation and metal filtering, which we detail in this manuscript. This achievement makes HP pyruvate MRI available to a wide biomedical community for fast metabolic imaging of living organisms. 

Abstract Demonstration of parahydrogen‐induced polarization effects in hydrogenations catalyzed by heterogeneous catalysts instead of metal complexes in a homogeneous solution has opened an entirely new dimension for parahydrogen‐based research, demonstrating its applicability not only for the production of catalyst‐free hyperpolarized liquids and gases and long‐lived non‐equilibrium spin states for potential biomedical applications, but also for addressing challenges of modern fundamental and industrial catalysis including advanced mechanistic studies of catalytic reactions and operando NMR and MRI of reactors. This essay summarizes the progress achieved in this field by highlighting the research contributed to it by our colleague and friend Kirill V. Kovtunov whose scientific career ended unexpectedly and tragically at the age of 37. His role in this research was certainly crucial, further enhanced by a vast network of his contacts and collaborations at the national and international level.