Development and Application of Novel Parahydrogen based NMR Techniques

• Applicant: Professor Dr. Gerd Buntkowsky
• Subject Area: Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405811162

• Final Report Year: 2023

Final Report Abstract

The joint project by the TU Darmstadt and the ITC Novosibirsk had two main objectives, namely (a) the development of a detailed understanding of the chemistry, spin-dynamics and theoretical foundations of parahydrogen-based NMR signal enhancement experiments like PHIP and SABRE and their optimization towards applications in analytical chemistry and (b) an evaluation and optimization of PHIP hyperpolarized biomarkers for applications in medical diagnostics and treatments. In the first objective a detailed theory of PHIP/SABRE experiments was developed, including a formulation of the SABRE-relay theory and the ODIP theory and an analysis of transient intermediates formed during the SABRE formation of the IMES-catalyst. Based on this analysis an experimental scheme to prolong the nuclear spin singlet life-time of the hydride protons by more than a factor of 10 from 2.2±0.1 s to 27.2±1.2 s was developed, which extends the application window of the hyperpolarization by the same factor. In addition, the two groups have demonstrated the feasibility of heteronuclear TOCSY by combining high-field NMR detection and spin mixing. Finally, a novel heterogeneous SABRE catalyst was synthesized and studied. Therefore, for the first time an Ir-NHC complex with a polymer unit substitution at the backbone of the N-Heterocyclic Carbenes (NHC) for SABRE hyperpolarization was employed. Owing to the polymer backbone it is possible to remove the catalyst from solution after the hyperpolarization of a target substrate has been generated. While the polymerization of the catalyst reduces its signal enhancement ε by about an order of magnitude compared to the monomeric units (from typically ε=200-300 to ε=20-40) the obtained signal enhancements are still substantial enough to reduce measurement times by factors of 400-1600. In the second objective, the potential of fumarate, an important tumor marker in the crab cycle, hyperpolarized by PHIP, for in-vivo MRI applications in cancer diagnostics and cancer treatment was investigated. The hyperpolarized singlet state of fumarate is generated from dicarboxylic acid by hydrogenation with p-H2, which is converted by fumarase to malate, which renders them NMR and MRI active. In a proof-of principle experiment we could show that this strategy works indeed and detected hyperpolarized malate signals of a phantom. The hyperpolarized fumarate can be purified by acid precipitation as a pure solid, and later redissolved at a chosen concentration in a clean aqueous solvent. It was found that it is possible to form hyperpolarized fumarate at several hundred millimolar concentrations, at 13C polarization levels of 30-45% and 28% of protons.

Publications

• Indirect Detection of Short-Lived Hydride Intermediates of Iridium N-Heterocyclic Carbene Complexes via Chemical Exchange Saturation Transfer Spectroscopy. The Journal of Physical Chemistry C, 123(26), 16288-16293.
  Knecht, Stephan; Hadjiali, Sara; Barskiy, Danila A.; Pines, Alexander; Sauer, Grit; Kiryutin, Alexey S.; Ivanov, Konstantin L.; Yurkovskaya, Alexandra V. & Buntkowsky, Gerd
  
• The application of novel Ir-NHC polarization transfer complexes by SABRE. The Journal of Chemical Physics, 151(24).
  Hadjiali, Sara; Bergmann, Marvin; Kiryutin, Alexey; Knecht, Stephan; Sauer, Grit; Plaumann, Markus; Limbach, Hans-Heinrich; Plenio, Herbert & Buntkowsky, Gerd
  
• Spin dynamics in experiments on orthodeuterium induced polarization (ODIP). The Journal of Chemical Physics, 153(11).
  Kozinenko, Vitaly P.; Kiryutin, Alexey S.; Knecht, Stephan; Buntkowsky, Gerd; Vieth, Hans-Martin; Yurkovskaya, Alexandra V. & Ivanov, Konstantin L.
  
• Theoretical description of hyperpolarization formation in the SABRE-relay method. The Journal of Chemical Physics, 153(16).
  Knecht, Stephan; Barskiy, Danila A.; Buntkowsky, Gerd & Ivanov, Konstantin L.
  
• Total Correlation Spectroscopy across All NMR-Active Nuclei by Mixing at Zero Field. The Journal of Physical Chemistry Letters, 11(17), 7291-7296.
  Zhukov, Ivan V.; Kiryutin, Alexey S.; Ferrage, Fabien; Buntkowsky, Gerd; Yurkovskaya, Alexandra V. & Ivanov, Konstantin L.
  
• Optimizing the Reaction Conditions for the Formation of Fumarate via Trans-Hydrogenation. Applied Magnetic Resonance, 53(3-5), 615-634.
  Wienands, Laura; Theiß, Franziska; Eills, James; Rösler, Lorenz; Knecht, Stephan & Buntkowsky, Gerd
  
• Parahydrogen‐Induced Polarization of Amino Acids. Angewandte Chemie International Edition, 60(44), 23496-23507.
  Pravdivtsev, Andrey N.; Buntkowsky, Gerd; Duckett, Simon B.; Koptyug, Igor V. & Hövener, Jan‐Bernd
  
• Rapid hyperpolarization and purification of the metabolite fumarate in aqueous solution. Proceedings of the National Academy of Sciences, 118(13).
  Knecht, Stephan; Blanchard, John W.; Barskiy, Danila; Cavallari, Eleonora; Dagys, Laurynas; Van Dyke, Erik; Tsukanov, Maksim; Bliemel, Bea; Münnemann, Kerstin; Aime, Silvio; Reineri, Francesca; Levitt, Malcolm H.; Buntkowsky, Gerd; Pines, Alexander; Blümler, Peter; Budker, Dmitry & Eills, James
  
• Singlet‐Contrast Magnetic Resonance Imaging: Unlocking Hyperpolarization with Metabolism**. Angewandte Chemie International Edition, 60(12), 6791-6798.
  Eills, J.; Cavallari, E.; Kircher, R.; Di Matteo, G.; Carrera, C.; Dagys, L.; Levitt, M. H.; Ivanov, K. L.; Aime, S.; Reineri, F.; Münnemann, K.; Budker, D.; Buntkowsky, G. & Knecht, S.
  
• Recent advances in the application of parahydrogen in catalysis and biochemistry. RSC Advances, 12(20), 12477-12506.
  Buntkowsky, Gerd; Theiss, Franziska; Lins, Jonas; Miloslavina, Yuliya A.; Wienands, Laura; Kiryutin, Alexey & Yurkovskaya, Alexandra