Stephan Berner1,2,3, Stephan Knecht1,4, Andreas Benjamin Schmidt1,4, Mirko Zimmermann1, Jürgen Hennig1, Dominik von Elverfeldt1, and Jan-Bernd Hövener4
1Department of Radiology, Medical Physics, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, 2DKTK, Freiburg, Germany, 3DKFZ, Heidelberg, Germany, 4Department of Radiology and Neuroradiology, Section Biomedical Imaging, MOIN CC University Medical Center Schleswig-Holstein, University of Kiel, Kiel, Germany
Synopsis
Hyperpolarization overcomes the biggest
limitation of MRI: its low sensitivity, and enables metabolite mapping. Hyperpolarized 13C magnetization can
be produced by transferring the spin order of parahydrogen into 13C by hydrogenation followed by a
sequence of 1H and 13C pulses. However, it is possible to hyperpolarize AA’X spin systems by two
pulses on 13C. Theoretical models were developed to describe the
polarization transfer and significant signal increase was observed for the
biomolecule succinate after spin order transfer directly in the magnet of a
commercial MRI system. The experimental data is well described by theoretical
calculations except for an overall scaling factor.
Introduction
Magnetic Resonance Imaging (MRI) is a powerful
tool in clinical diagnosis despite its low sensitivity that is caused by the low
thermal polarization of the order of 10-5. For many (spectroscopic)
applications the signal is simply too low. This issue is partially resolved by
hyperpolarization methods, whose signal enhancement enables the monitoring of
metabolism. Spin Order Transfer (SOT) sequences were developed to transform
spin order from parahydrogen into 13C
magnetization by appropriate radiofrequency pulses on 1H and 13C,
free evolution intervals, and heteronuclear decoupling schemes during
hydrogenation. However, it is possible to hyperpolarize an AA’X spin system
with a much simpler experiment by applying a single 90° 13C pulse followed
by a refocusing pulse directly after hydrogenation without the need for
decoupling [1]. Here we present a theoretical model and first experimental
data of a biologically relevant molecule obtained in a preclinical MR system.
Methods
1-13C,2,3-2H2-Succinate
was formed by catalytic hydrogenation of fumarate under PASADENA [2] conditions and polarized by means of SAMBADENA [3] in the magnet bore of a preclinical 7T MR
system (Bruker Biospec, Germany). The pulse sequence 90x° – ts/2
– 180° – ts/2 – acquisition (free evolution time ts) was applied after a time
duration thyd after the
onset of the hydrogenation. The parameters ts
and thyd were
experimentally optimized, a mathematical model was developed [3] and fitted to the data points. Quantum mechanical
simulations were carried out to predict the theoretical polarization yield as a
function of ts. The
process of hydrogenation was considered by averaging the density matrix over thyd. The resulting density
matrix was manipulated by radio frequency pulses and evolved in time under the
Hamiltonian of an AA’X spin system. Relaxation effects were neglected. Additionally,
the effect of erroneous flip angles on the polarization yield was calculated. The
experimental polarization yield was quantified by comparison with a thermally
polarized reference, assuming a parahydrogen
fraction of 100% and complete hydrogenation.
Results
The highest theoretical polarization yield was PTheory = 48% for ts = 68 ms. The greatest signal
enhancement observed experimentally was 1400-fold, corresponding to a polarization
level of ≈ 0.83% for ts =
60 ms and 70 ms. The calculated polarization yield as function of ts was well reproduced
experimentally, except for a constant scaling factor of 57.83 (Fig. 1). The optimal hydrogenation
duration thyd was found to
be between 3 s and 6 s (Fig. 2). By fitting a kinetic model to the data points,
the relaxation constant of the para
order Tpara and the
hydrogenation constant Tcat were
determined to Tpara = (13
± 5) s and Tcat =(1.4 ±
0.9) s.
Discussion
In only a few seconds, a significant 13C-signal increase was experimentally
achieved in the bore of an MR system, although with an amplitude of
approximately 58-times less than predicted which is too little for biomedical
application. The missing signal may be attributed to relaxation effects,
experimental errors and incomplete hydrogenation. For deviations of 50% of the
nominal flip angle, the theoretical polarization yield is still greater than
25%. Note that polarization levels of about 7% were achieved by means of
Goldman’s sequence [4] (theoretical polarization: 99%) using the same
setup [5].
Conclusion
In comparison to other transfer methods, the
treated two-pulse sequence is much simpler, faster, and more robust against
erroneous flip angles and off resonant pulses. However, the high
theoretically predicted polarization yields of about 50% could, so far, not be
achieved experimentally. The low experimentally observed signal enhancements
may suggest either experimental errors or a significant effect that is not yet
considered in the theoretical model. Note that this sequence is of interest for
MR systems that cannot play out either pulses on two channels or demanding
decoupling sequences.
Acknowledgements
Support by
the DFG (HO 4604/1-1 and HO 4604/2-1), the DKFZ/DKTK and the Heinrich-Böll-Stiftung
(ABS, P131623) and the contribution of the COST Action TD1103 is greatly
acknowledged.
References
-
Haake, M., Natterer, J. & Bargon,
J. Efficient NMR Pulse Sequences to Transfer the Parahydrogen-Induced
Polarization to Hetero Nuclei. J. Am. Chem. Soc. 118, 8688–8691
(1996)
- Bowers, C. R. & Weitekamp, D. P.
Parahydrogen and synthesis allow dramatically enhanced nuclear alignment. J.
Am. Chem. Soc. 109, 5541–5542 (1987).
- Schmidt, A. B. et al.
Liquid-state carbon-13 hyperpolarization generated in an MRI system for fast
imaging. Nat. Commun. 8, ncomms14535 (2017).
- Goldman, M. & Jóhannesson, H.
Conversion of a proton pair para order into 13C polarization by rf irradiation,
for use in MRI. Comptes Rendus Phys. 6, 575–581 (2005).
- Stephan Berner, Andreas Schmidt,
Schimpf Waldemar & Jan-Bernd Hövener. Hyperpolarization of a biomolecule to
7% in an MRI using SAMBADENA. Proceedings
of EMIM 2017