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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 Hyperpolarized magnetic resonance imaging (HP‐MRI) has emerged as a powerful tool in molecular imaging, providingin vivo, real‐time insights into metabolic pathways without ionizing radiation. Signal Amplification by Reversible Exchange (SABRE) represents a promising hyperpolarization technique, leveraging parahydrogen to enhance MRI signals. In this concept, we delineate the evolution of SABRE and landmark papers that have enabled us recently to produce biocompatible and low‐cost hyperpolarized pyruvate within minutes forin vivometabolic imaging, showcasing SABRE′s potential for preclinical and near‐future clinical settings. Looking ahead, with ongoing efforts focused on optimizing polarizer technology and expanding applications beyond pyruvate, we envision SABRE as a key player in the research and application of HP‐MRI due to its simplicity and throughput. 

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 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 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 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.