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1. Solvent Effects in Hyperpolarization of ¹⁵ N Nuclei in [ ¹⁵ N ₃ ]Metronidazole and [ ¹⁵ N ₃ ]Nimorazole Antibiotics via SABRE‐SHEATH**

   https://doi.org/10.1002/anse.202400045  

   Yi, Anna_P; Salnikov, Oleg_G; Burueva, Dudari_B; Chukanov, Nikita_V; Chekmenev, Eduard_Y; Koptyug, Igor_V (August 2024, Analysis & Sensing)

   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. 

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2. Development of Dissolution Dynamic Nuclear Polarization of [ ¹⁵ N ₃ ]Metronidazole: A Clinically Approved Antibiotic

   https://doi.org/10.1002/anie.202219181  

   Guarin, David O.; Joshi, Sameer M.; Samoilenko, Anna; Kabir, Mohammad S. H.; Hardy, Erin E.; Takahashi, Atsush M.; Ardenkjaer‐Larsen, Jan H.; Chekmenev, Eduard Y.; Yen, Yi‐Fen (June 2023, Angewandte Chemie International Edition)

   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. 

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3. Terminal Diazirines Enable Reverse Polarization Transfer from ¹⁵ N ₂ Singlets

   https://doi.org/10.1002/anie.201904026  

   Zhang, Guannan; Colell, Johannes F. P.; Glachet, Thomas; Lindale, Jacob R.; Reboul, Vincent; Theis, Thomas; Warren, Warren S. (July 2019, Angewandte Chemie International Edition)

   Abstract Diazirine moieties are chemically stable and have been incorporated into biomolecules without impediment of biological activity. The¹⁵N₂labeled diazirines are appealing motifs for hyperpolarization supporting relaxation protected states with long‐lived lifetimes. The (‐CH¹⁵N₂) diazirine groups investigated here are analogues to methyl groups, which provides the opportunity to transfer polarization stored on a relaxation protected (‐CH¹⁵N₂) moiety to¹H, thus combining the advantages of long lifetimes of¹⁵N polarization with superior sensitivity of¹H detection. Despite the proximity of¹H to¹⁵N nuclei in the diazirine moiety,¹⁵NT₁times of up to (4.6±0.4) min and singlet lifetimesT_sof up to (17.5±3.8) min are observed. Furthermore, we found terminal diazirines to support hyperpolarized¹H₂singlet states in CH₂groups of chiral molecules. The singlet lifetime of¹H singlets is up to (9.2±1.8) min, thus exceeding¹HT₁relaxation time (at 8.45 T) by a factor of ≈100. 

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4. ³¹ P spin–lattice and singlet order relaxation mechanisms in pyrophosphate studied by isotopic substitution, field shuttling NMR, and molecular dynamics simulation

   https://doi.org/10.1039/D2CP03801C  

   Korenchan, David E.; Lu, Jiaqi; Sabba, Mohamed; Dagys, Laurynas; Brown, Lynda J.; Levitt, Malcolm H.; Jerschow, Alexej (October 2022, Physical Chemistry Chemical Physics)

   Nuclear spin relaxation mechanisms are often difficult to isolate and identify, especially in molecules with internal flexibility. Here we combine experimental work with computation in order to determine the major mechanisms responsible for 31 P spin–lattice and singlet order (SO) relaxation in pyrophosphate, a physiologically relevant molecule. Using field-shuttling relaxation measurements (from 2 μT to 9.4 T) and rates calculated from molecular dynamics (MD) trajectories, we identified chemical shift anisotropy (CSA) and spin–rotation as the major mechanisms, with minor contributions from intra- and intermolecular coupling. The significant spin–rotation interaction is a consequence of the relatively rapid rotation of the –PO 3 2− entities around the bridging P–O bonds, and is treated by a combination of MD simulations and quantum chemistry calculations. Spin–lattice relaxation was predicted well without adjustable parameters, and for SO relaxation one parameter was extracted from the comparison between experiment and computation (a correlation coefficient between the rotational motion of the groups). 

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5. ¹⁵ N NMR Hyperpolarization of Radiosensitizing Antibiotic Nimorazole by Reversible Parahydrogen Exchange in Microtesla Magnetic Fields

   https://doi.org/10.1002/anie.202011698  

   Salnikov, Oleg G.; Chukanov, Nikita V.; Svyatova, Alexandra; Trofimov, Ivan A.; Kabir, Mohammad S. H.; Gelovani, Juri G.; Kovtunov, Kirill V.; Koptyug, Igor V.; Chekmenev, Eduard Y. (December 2020, Angewandte Chemie International Edition)

   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 toP_15Nof 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. 

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