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1. Synthetic Approaches for 15 N‐Labeled Hyperpolarized Heterocyclic Molecular Imaging Agents for 15 N NMR Signal Amplification by Reversible Exchange in Microtesla Magnetic Fields

   https://doi.org/10.1002/chem.202100212  

   Chukanov, Nikita V. ; Shchepin, Roman V. ; Joshi, Sameer M. ; Kabir, Mohammad S. H. ; Salnikov, Oleg G. ; Svyatova, Alexandra ; Koptyug, Igor V. ; Gelovani, Juri G. ; Chekmenev, Eduard Y. ( May 2021 , Chemistry – A European Journal)

   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.

    

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2. Synthesis and 15 N NMR Signal Amplification by Reversible Exchange of [ 15 N]Dalfampridine at Microtesla Magnetic Fields

   https://doi.org/10.1002/cphc.202100109  

   Chukanov, Nikita V. ; Salnikov, Oleg G. ; Trofimov, Ivan A. ; Kabir, Mohammad S. H. ; Kovtunov, Kirill V. ; Koptyug, Igor V. ; Chekmenev, Eduard Y. ( April 2021 , ChemPhysChem)

   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.

    

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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)

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

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

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

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

   https://doi.org/10.1002/ange.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)

   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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