Dissolution Dynamic Nuclear Polarization at Room Temperature

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A: Spectroscopy, Photochemistry, and Excited States

Dissolution Dynamic Nuclear Polarization at Room Temperature using Photoexcited Triplet Electrons Makoto Negoro, Akinori Kagawa, Kenichiro Tateishi, Yoshiki Tanaka, Tomohiro Yuasa, Keigo Takahashi, and Masahiro Kitagawa J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b01415 • Publication Date (Web): 13 Apr 2018 Downloaded from http://pubs.acs.org on April 15, 2018

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The Journal of Physical Chemistry

Dissolution Dynamic Nuclear Polarization at Room Temperature using Photoexcited Triplet Electrons Makoto Negoro*[a,b], Akinori Kagawa [a], Kenichiro Tateishi [c], Yoshiki Tanaka [a], Tomohiro Yuasa [a], Keigo Takahashi [a], and Masahiro Kitagawa [a] [a] Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan [b] PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan [c] RIKEN Nishina Center for Accelerator-Based Science Wako, Saitama 351-0198 (Japan)

Supporting Information Placeholder ABSTRACT: Dissolution dynamic nuclear polarization (DNP) has recently gained attention as a method to enhance the sensitivity of liquid NMR spectroscopy and MRI. Here, we demonstrate dissolution of the sample hyperpolarized by DNP using photoexcited triplet electrons in 0.38 T at room temperature. The achieved polarization of 0.8% is 6100 times as high as that at thermal equilibrium in the condition. The result is an important step for DNP using photoexcited triplet electrons to become widely used in chemical and biomedical research.

1. Introduction NMR spectroscopy and MRI can noninvasively analyze molecules deep inside materials as well as the human bodies, and are now widely used in various fields such as chemistry, materials science, pharmacy, life sciences, and healthcare1,2. NMR signal intensity and sensitivity are proportional to nuclear spin polarization. At room temperature, in a strong magnetic field typically used in NMR spectroscopy and MRI, the proton spin polarization is 10-4 to 10-5, since the Zeeman energy is five orders of magnitude lower than the thermal energy. The low polarization results in the sensitivities of NMR spectroscopy and MRI lower than those of methods using light or X-rays. Overhauser discovered DNP, a means of transferring spin polarization to nuclei from unpaired electrons, which have 660 times the Zeeman energy of proton spins3. At first, quantum physics including high-energy4 and condensed-matter physics5 utilized bulk solid samples hyperpolarized with DNP at extremely low temperatures in high magnetic fields. Recently, high-sensitivity solid-state NMR of glassy samples polarized at very low temperature was demonstrated at high resolution with magic angle spinning (MAS), which opened the way for applications of DNP to chemical and biological analysis6,7. In 2003, Ardenkjaer-Larsen et al. developed dissolution DNP, a method for hyperpolarizing liquids by dissolving solids polarized with DNP at extremely low temperatures in high magnetic fields in hot aqueous solutions8. Transient chemical phenomena of various molecules have been studied in liquid-state NMR spectroscopy with dissolution DNP9. By injecting molecular sensors with hyperpolarized nuclear spins, real-time in vivo metabolic imaging was realized10. One of the most promising applications of dissolution DNP is the assessment of cancer therapy by metabolic imaging11,12.

In conventional DNP, unpaired electrons in free radicals are polarized to 660 times the polarization of proton spins by thermal equilibration, a classical process. The polarization enhancement factor of conventional DNP is, in principle, limited to at most 660 for proton spins, that is, the thermal electron spin polarization limit. In order to obtain a nuclear spin polarization of around 10%, dissolution DNP is typically carried out at an extremely low temperature (~1 K) and in the high magnetic field (> 3 T) generated by a superconducting magnet. Thus, the instrumentation is large and expensive to be installed in small laboratories and hospitals although the proton polarization of ~90% are currently available13. If dissolution DNP at room temperature with smaller and lower-cost instrumentation becomes available, dissolution DNP and its applications will become more widely used. There have been efforts to achieve high polarization at room temperature by DNP. In 2017, with conventional DNP at room temperature in 3.4 T, the polarization of a liquid has been enhanced to 0.6%, which is near the theoretical limit14. One way to overcome the thermal electron limit imposed by thermally polarized state of unpaired electrons is to use photoexcited triplet state of electrons instead15-20. In photoexcited π-conjugated molecules, electron spins are spontaneously polarized to more than 10% through the intersystem crossing from the photoexcited singlet to triplet states, a quantum process. The triplet state electron spin polarization is insensitive to temperature and magnetic field strength. With DNP using photoexcited triplet electrons, which is referred to as triplet-DNP, we have achieved a 1H spin polarization of 34% at room temperature in 0.4 T, which gives a polarization enhancement factor of 250,000 far beyond 660[21]. The polarization is 33,000 times higher than thermal equilibrium at room temperature in 3 T, the typical condition used in MRI. To date, triplet-DNP has been employed only in branches of quantum physics, e.g., nuclear physics22, neutron physics23, and quantum information science24. Highly sensitive solid-state NMR of a glassy matrix with triplet-DNP has recently been demonstrated, which opened the way for the application of triplet-DNP to chemical analysis25. All samples hyperpolarized by triplet-DNP have so far been waterinsoluble solids. By contrast, in the present work, we have succeeded in triplet-DNP of samples of benzoic acid (BA), which is water-soluble. Then, we have demonstrated dissolution DNP at room temperature.

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2. Experimental and results All experiments were carried out in 0.38 T at room temperature. We used solid-state samples of BA, rarely doped with pentacene. In the samples, the photoexcited triplet electron spins in pentacene are polarized to 23%[26] with the quantum process (Figure 1a). During the lifetime of the photoexcited triplet state, i.e., ~100 µs, we coherently transfer the polarization to 1H spins with DNP using a pulsed microwave, via the so-called integrated solid effect (ISE)15-17,21,27. By repeating the sequence of photoexcitation and pulsed DNP at 20-ms intervals (Figure 1b), we increased the 1H spin polarization of the whole sample, until the buildup and the 1H spin lattice relaxation reached equilibrium. We used a dye laser with a wavelength of 590 nm as a light source. A low-cost and compact light source, such as a flashlamp, can be an alternative and has already been used to excite pentacene in the study on MASER amplifier28. A static magnetic field of 0.38 T was generated by a compact electromagnet. The X-band microwave apparatus has lower cost and is easier to handle than the submillimeter one used in conventional DNP.

NMR signals from the hyperpolarized liquid, as shown in Figure 3. In 0.38 T, we injected a 1 M hot deuterated solution of sodium carbonate (130 mg) 20 s after triplet-DNP, while 1H NMR signals were repeatedly measured by 15° pulses at intervals of 1 s. The spectra before injection are broad, owing to the dipolar interactions in solids. The spectra after injection are sharp because of the motional narrowing in liquids. The areas under the spectra before and after injection are almost the same. On the basis of these experiments, we conclude that the sample dissolved rapidly, without loss of polarization. In the liquid samples, pentacene was precipitated. It is easy to filter out pentacene.

Figure 2. Polarization buildup of powder and crystalline samples. The pentacene concentration is 0.04 mol% in all samples. Orange and blue are the powder and crystal of BA doped with pentaceneh14, while red and black are the powder and crystal of BA-d1 doped with pentacene-d14.

Figure 1. Energy diagram of pentacene doped into BA (A), pulse sequence for DNP and NMR detection (B), and pentacene and BA-d1 (C). In Figure 2, we show the buildup curves of 1H spin polarizations in samples of BA with 0.04 mol% pentacene (Supporting Information Available). For powder sample with 0.04 mol% pentacene, we obtained a 1H spin polarization of 0.35% (orange). The 1 H spin lattice relaxation time (T1) of BA in powder samples was 5 min. In the sample, the motion of carboxyl hydrogen is the main source of T1 relaxation. The T1 of BA-d1, in which carboxyl hydrogen is regioselectively deuterated (Figure 1c), for a powdered sample was 7 min. For a powder sample of BA-d1 doped with 0.04 mol% pentacene-d14, we achieved a 1H spin polarization of 0.8% after performing triplet-DNP for 10 min at room temperature (red in Figure 2). The purpose for using deuterated pentacene is to suppress the proton relaxation induced by triplet electrons as mentioned in the reference21. The polarization achieved was higher than the abovementioned result obtained by conventional DNP at room temperature14. It was 6100 and 780 times as high as the thermal polarization at room temperature in 0.38 and 3.0 T, respectively. We dissolved the deuterated powder sample (3.6 mg) after conducting triplet-DNP for 10 min (red in Figure 2) and obtained

Figure 3. The results of dissolution DNP. A hot aqueous solution was injected 20 s after triplet-DNP, while the 1H magnetization was measured with 15° pulses repeatedly, at intervals of 1 s. Time t is the interval from just finishing triplet-DNP to the NMR measurement. For BA-d1 doped with pentacene-d14 samples, the maximum polarization of the powder (0.8%, red in Figure 2) is lower than that of a single crystal with the orientation in which the highest polarization is obtained (2.4%, black). Both the electron spin polarization and EPR frequency depend on the orientation of molecule with respect to the static field. In the powder sample, therefore, only a small fraction of molecules have high electron polarization and participate in the DNP process29.

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The Journal of Physical Chemistry Corresponding Author *[email protected] 3. Discussion The gap of the polarizations between the single-crystal BA and p-terphenyl21 can be explained by the three- and ten-fold difference in, respectively, the electron polarization and 1H spin T1. It is important to understand the reason why the electron spin polarization of the pentacene doped into benzoic acid is 3 times lower than that in p-terphneyl. There may exist a way to avoid the decrease with slight decoration of benzoic acid. Also, the gap will be bridged with developing another kind of triplet molecules with a higher polarization robust against host and laser with a higher repetition rate. We have not achieved the dissolution of the single crystal samples yet. In order to dissolve bulk crystals, we need more time than powders, < 1s. If we use a stack of thin films of single crystals with air gaps, we can dissolve it instantaneously. We have already demonstrated that the polarization of a thin film sample with a thickness of 10 µm was as high as that of the bulk crystal30. The sample weight for dissolution DNP was 3.6 mg and the laser power was 500 mW. The photon number per unit should be scaled up in proportion to the number of pentacene contained in the sample. The demonstration with a larger sample, > 1 g, and a stronger laser is an important future work toward medical applications. Hyperpolarized BA has already been used as a molecular spin sensor in an in vitro application31, where 13C spin hyperpolarization was exploited in a superconducting magnet for high resolution. It is possible for this application to transfer polarization from 1H to 13C spins with field cycling instrumentation from an electromagnet to a superconducting magnet32. BA is just the first molecule to be succeeded in dissolution DNP using triplet electrons. Various molecules soluble in BA can be hyperpolarized. If triplet molecules soluble in typical organic solvent or water is used, a wider variety of molecules can be hyperpolarized. Unfortunately pentacene is hardly soluble. We recently demonstrated hyperpolarization of glassy matrices of ethanol:water and toluene:benzene doped with a solubilized pentacene derivative, although the polarization enhancement factor was, now, less than 100, much lower than that in the present work.

4. Conclusion By using dissolution DNP and photoexcited triplet electrons at room temperature, we achieved enhancement of liquid-state NMR signals beyond the thermal electron limit. This breakthrough will open the way for triplet-DNP applications in pharmaceutical, medical, and life sciences, as well as in healthcare, in a manner similar to conventional DNP.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. The buildup of 1H spin polarizations in powder samples of BA with various pentacene concentrations is shown in Figure S1. How to determine the enhancement factor and the spin polarization is also shown. (PDF).

AUTHOR INFORMATION

Author Contributions M.N., A.K. and M.K. designed research; M.N., A.K., K.Tateishi Y.T., T.Y and K.Takahashi performed experiments; M.N., A.K. and Y.T. analyzed data; M.N., A.K., K.Tateishi, Y.T. and T.Y. developed experimental instrumentation; M.N., A.K. and M.K. wrote the manuscript.

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We thank Kazuyuki Takeda for supplying deuterated pentacene. This work was supported by CREST, JST Grand Number JPMJCR1672; JSPS KAKENHI Grant Number 26620009.

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