Simulationen und Neuartige Katalytische Verfahren zur Empfindlichkeitssteigerung von Biomedizinischen Anwendungen der Magnetischen Resonanz durch Para-Wasserstoff Induzierte Kernspinpolarisation
Zusammenfassung der Projektergebnisse
Bommerich group. The first focus of the work consisted in the implementation of the technical infrastructure in close collaboration with the Buntkowsky and Bernarding group. A unit for parahydrogen enrichment and the workflow were implemented for all groups. Similarly, the procedures for PHIP MRI on the Bruker animal scanner (Bruker 47/20) at the LIN were jointly optimized including the construction of a 1H/13C coil. A longer delay of some working packages was caused by the relocation of the complete Leibniz Institute into a new building and a subsequent repair of the Bruker MR tomograph. After determining the influence of experimental parameters and the reproducibility of PHIP transfer in the according substances the group studied the influence of different solvents on the PHIP signal enhancement in order to move towards more biocompatible substrate/solvent-mixtures. One part of this subproject dealt with the analysis of different catalysts and the study of further biocompatible markers and substances with a high potential for medical applications. Four different catalysts were tested and the achieved signal enhancements compared using 4-pentynoic acid as a model substance. All catalysts enabled the transfer of PHIP by hydrogenation. These catalysts generally can be easily extracted from the solvent/substrate mixture via ionic exchanger. First results of a phase extraction procedure suggest that a further optimization using a 2-phase extraction may provide an interesting alternative to separate the hyperpolarized products from the solution containing the catalyst. Pentynoic acid is a very interesting substance as it serves as a model for the hyperpolarization of muchused anti-epileptic drugs such as valproate or vigabatrin. The highest signal enhancements were achieved in acetone or alcohols while D2O led to a rather moderate signal enhancement. Hyperpolarization was also observable on 13C where higher temperatures led to an increased signal enhancement in mixtures of D2O/alcohol as solvents. Bio-tolerable addition of ethanol may therefore provide a strategy to increase PHIP both on 1H and 13C. Most surprisingly a strong prolongation of the relaxation of the hyperpolarized olefinic protons to about 36-42 sec was observed as compared to the T1 relaxation of the same protons, detected from standard Boltzmann-Polarization, which exhibited only about 7-9 sec. The unexpected finding is not yet fully understood and will be analyzed in the forthcoming project period. The approach was successfully used to hyperpolarize 2-propyl-4-pentenoic acid and the next hydrogenation product valproate which was thus generated for the first time in a hyperpolarized form. Hyperpolarization of many drugs and medical relevant molecules such as amino acids like the important neurotransmitter GABA is difficult due to the donor character of the functional groups that usually act as ligands at the active catalytic sites. Here, protonation of the starting material by a decrease of the pH led to the first successful hyperpolarization of Allylglycine, Vigabatrine und GABA. The hyperpolarization of ethanol was realized in close cooperation with the Bernarding group (for details see above). The starter substance vinyl-acetate was further studied with respect to the transfer of the PHIP to 13C as similar molecular structures can be found in different physiologically relevant molecules able to cross the brainblood barrier. Similar to prior results with other substrates hyperpolarization is strongest in acetone as solvent but still detectable in alcohol/D2O mixtures. The next step towards the development of molecular imaging markers was taken by studying substances such as a fluorinated bis(phenylethynyl)benzene derivative and diphenylacetylene leading to hydrogenation products with similar structures compared to biomarkers already used for imaging of Alzheimer plaques. For the first time PHIP could be successfully transferred to 19F nuclei of this analogue substance. PHIP MRI was implemented on a 4.7 T Bruker animal scanner (BioSpec47/20) and images of hyperpolarized 4-pentenoic-acid (1H) and hyperpolarized ethyl acetate (13C) could be acquired successfully proving the overall approach.
Projektbezogene Publikationen (Auswahl)
- Para-hydrogen induced polarization in homogenous phase – an example how ionic liquids affect homogenization and thus activation of catalysts. Phys. Chem. Chem. Phys., 11, (2009), 9170–9175
T. Gutmann, M. Sellin, H. Breitzke, A. Stark, G. Buntkowsky
- Hyperpolarized 19F-MRI: para-hydrogen induced polarization and field variation enabling 19F-MRI at low spin density. Phys.Chem.Chem.Phys., 12, (2010), 10309-10312
U. Bommerich, T. Trantzschel, S. Mulla-Osman, G. Buntkowsky, J. Bargon, J. Bernarding
- Understanding the leaching Properties of heterogenized Catalysts: a combined Solid-State and PHIP NMR Study. Solid-State NMR., 38, (2010), 90-96
T. Gutmann; T. Ratajczyk; Y. Xu; H. Breitzke; A. Gruenberg; S. Dillenberger; U. Bommerich; Th. Trantzschel; J. Bernarding, G. Buntkowsky
- New investigations of technical rhodium and iridium catalysts in homogeneous phase employing Para-Hydrogen Induced Polarization.Solid-State NMR.,40, (2011), 88–90
T. Gutmann, T. Ratajczyk, S. Dillenberger, Y. Xu, A. Grünberg, H. Breitzke, U. Bommerich, T. Trantzschel, J. Bernarding, G. Buntkowsky
- Para-hydrogen induced polarization in face of ketoenoltautomerism: proof of concept with hyperpolarized ethanol. Phys. Chem. Chem. Phys., 14, (2012), 5601-5604
Th. Trantzschel, J. Bernarding, M. Plaumann, D. Lego, T. Gutmann, T. Ratajczyk, S. Dillenberger, G. Buntkowsky, J. Bargon, U. Bommerich
(Siehe online unter https://doi.org/10.1039/c2cp40272f) - Time Domain Para-Hydrogen Induced Polarization. Solid-State NMR., 43-44, (2012), 14-21
T. Ratajczyk, T. Gutmann, S. Dillenberger, S. Abdulhussaein, J. Frydel, H. Breitzke, U. Bommerich, Th. Trantzschel, J. Bernarding, P. Magusin, G. Buntkowsky
(Siehe online unter https://doi.org/10.1016/j.ssnmr.2012.02.002) - Application of Para-hydrogen Induced Polarization to Unprotected Dehydroamino Carboxylic Acids. Appl. Magn. Res., 44, (2013), 267-278
Th. Trantzschel, M. Plaumann, J.Bernarding, D.Lego, T. Ratajczyk, S. Dillenberger, G. Buntkowsky, J. Bargon, U. Bommerich
(Siehe online unter https://doi.org/10.1007/s00723-012-0391-0) - NMR Studies of the Reaction Path of the o-H2/p-H2 Spin Conversion Catalyzed by Vaska's Complex in the Solid-State; Appl. Magn. Res., 44, (2013), 247-265
J. Matthes, S. Gründemann, G. Buntkowsky, B. Chaudret, H.-H. Limbach
(Siehe online unter https://doi.org/10.1007/s00723-012-0395-9) - Parahydrogen-Induced Polarization Transfer to 19F in Perfluorocarbons for 19F NMR and MRI. Chem. Eur. J. 19, 6334 – 6339
M. Plaumann, U. Bommerich, T. Trantzschel, D. Lego, S. Dillenberger, G. Sauer, J. Bargon, G. Buntkowsky, J. Bernarding
- PHIP-Label: Parahydrogen-Induced Polarization in Propargylglycine-Containing Synthetic Oligopeptides, Chem.Comm. (2013), 49,7839-7841
M. Tischler, G. Sauer, A.Heil, D. Nasu, M. Empting, D. Tietze, S. Voigt, H. Weidler, T. Gutmann, O. Avrutina, H. Kolmar, T. Ratajczyk, G. Buntkowsky
(Siehe online unter https://doi.org/10.1039/c3cc43978j) - Parahydrogen-induced polarization of carboxylic acids: a pilot study of valproic acid and related structures. NMR Biomed., (2014), 27, 810 – 816
D. Lego, M.Plaumann ,T.Trantzschel, J. Bargon, H. Scheich, G. Buntkowsky, T. Gutmann, G. Sauer, J. Bernarding, U. Bommerich
(Siehe online unter https://doi.org/10.1002/nbm.3123) - Synthesis, Solid State NMR-Characterization and Application of a novel Wilkinson’s type immobilized Catalyst for hydrogenation reactions, Chemistry Eur.J., (2014), 20, 1159-1166
S. Abdulhussain, H. Breitzke, T. Ratajczyk, A. Grünberg, M. Srour, D. Arnaut, H. Weidler, U. Kunz, H.J. Kleebe, U. Bommerich, J. Bernarding, T. Gutmann, G. Buntkowsky
(Siehe online unter https://doi.org/10.1002/chem.201303020)
