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Boosting SABRE-SHEATH hyperpolarization with Coherent Control of Spin Dynamics1Chemistry, Duke University, Durham, NC, United States, 2Physics, Chemistry, BME, Radiology, Duke University, Durham, NC, United States
Synopsis
Signal Amplification By Reversible Exchange (SABRE) is a parahydrogen based hyperpolarization modality that is particularly simple, low-cost, and fast or even continuous. A more recent variant, SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) enables targeting 15N and 13C nuclei in a wide range of substrates, where hyperpolarization lifetimes can be particularly long. However, both SABRE and SABRE-SHEATH are limited by the incoherent nature of the hyperpolarization transfer process. Here we describe a pulsed variant of SABRE-SHEATH that takes coherent control over the spin dynamics and more than doubles achievable hyperpolarization levels. In addition, the pulsed SABRE-SHEATH experiments provide a new way of probing the hyperpolarization transfer, shedding new light on the limiting factors of this emerging technology.
INTRODUCTION
Signal Amplification By Reversible Exchange (SABRE) is a parahydrogen based hyperpolarization modality that is particularly simple, low-cost, and fast or even continuous.1 A more recent variant, SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) enables targeting 15N and 13C nuclei in a wide range of substrates, where hyperpolarization lifetimes can be particularly long. 2, 3 Fundamentally, SABRE and SABRE-SHEATH rely on reversible exchange reactions of parahydrogen and substrate with a polarization transfer complex (PTC, see Fig. 1). On the PTC hyperpolarization is transferred from parahydrogen to substrates if the magnetic field is selected adequately. (~65 G for SABRE, ~5 mG for SABRE-SHEATH). However, the reversible binding and desorption events are stochastically distributed, therefore the spin dynamics that lead to hyperpolarization transfer are incoherent, and the resulting hyperpolarization is just an average of the oscillating spin dynamics. Here we show, that we can take coherent control of SABRE-SHEATH polarization transfer by pumping the mG magnetic field. This leads to more than double in achievable hyperpolarization levels and provides a new method to study the hyperpolarization transfer events, which reveals critical insights into current limitations of the emerging technology.METHODS
Parahydrogen is bubbled through room temperature solutions where spin order is transferred from parahydrogen to substrates using a hyperpolarization transfer catalyst as depicted in Fig. 1. The hyperpolarization transfer to heteronuclei (in this case nitrogen-15) is most efficient at magnetic fields of about 5 mG established in µ-metal shields.2 (see Fig. 1b) Up till now, all reported SABRE-SHEATH experiments were conducted at constant magnetic fields. We have designed a system to stroboscopically pump the low magnetic field. This strategy enables coherent evolution of the hyperpolarization transfer. As depicted in Fig. 2, we vary the length of the 5 mG pulses (τp) between 1 and 100 ms. In between the pulses, we use a higher hyperpolarization storage field, which does not allow for further spin evolution but stores the hyperpolarization along the applied magnetic field. This delay (τd) allows the polarization transfer to “recharge” with fresh parahydrogen, so that the following 5 mG pulse has a maximized amount of spin order available. τd was varied between 1 ms and 5 s. Each data point in Fig. 2b or Fig 2c, is the result of applying a train of the mG pulses for a total time of 90 s. After this time, the sample is transferred into a high-field NMR spectrometer for detection with a simple pulse-acquire sequence for each data point.RESULTS
As can be seen in Fig. 2b, the stroboscopically pumped signals can significantly exceed the constant field implementation, which has been normalized to 1. Furthermore, it is also apparent that we can probe the hyperpolarization transfer dynamics with the stroboscopically pumped approach. We directly observe the oscillations produced by the coherent spin evolution of all PTCs. To acquire the data presented in Fig. 2c. the 5 mG pulse was set to τp=22 ms (the first maximum) and then τd (the delay between pulses) was optimized. As can be seen, a maximum is obtained at τd = 350 ms. This is a surprisingly long value and indicates that the “recharging process” of the PTC takes much longer than expected from literature documented exchange rates or average complex lifetimes (tlife=1/kex), which are on the order of 40 ms = 1/(25 s‑1).DISCUSSION
We identified a possibility to take coherent control of the SABRE-SHEATH spin dynamics. This enables more than doubling of hyperpolarization levels. (Polarization levels of ~5% with constant field, are boosted to above 10% with the pumped implementation.) In addition, the coherent control, using the stroboscopically pumped pulses, enables direct monitoring of the hyperpolarization transfer dynamics and gives kinetic insights pointing to critical limitations of SABRE-SHEATH hyperpolarization schemes that were not accessible before. For example, we can now probe the catalyst “recharging dynamics” and found evidence that this process is a major limiting factor that we can now aim to address.CONCLUSION
SABRE-SHEATH is emerging as a simple and versatile hyperpolarization scheme that works directly in room temperature solutions and hyperpolarizes a widening range of substrates. SABRE-SHEATH can be repeated many times on the same sample or even be implemented in continuous mode. With the presented stroboscopically pumped implementation we boost hyperpolarization levels significantly, which is important for future applications that include the examination of fundamental biophysics as well as biomolecular imaging to probe metabolic diseases.Acknowledgements
We thank the NSF for funding via grant NSF-CHE 1665090.References
1. Adams, R.W., Aguilar, J.A., Atkinson, K.D., Cowley, M.J., Elliott, P.I., Duckett, S.B., Green, G.G., Khazal, I.G., Lopez-Serrano, J. & Williamson, D.C. Reversible interactions with para-hydrogen enhance NMR sensitivity by polarization transfer. Science 323, 1708-11 (2009).
2. Theis, T., Truong, M.L., Coffey, A.M., Shchepin, R.V., Waddell, K.W., Shi, F., Goodson, B.M., Warren, W.S. & Chekmenev, E.Y. Microtesla SABRE Enables 10% Nitrogen-15 Nuclear Spin Polarization. J. Am. Chem. Soc. 137, 1404-1407 (2015).
3. Theis, T., Ortiz, G.X., Jr., Logan, A.W., Claytor, K.E., Feng, Y., Huhn, W.P., Blum, V., Malcolmson, S.J., Chekmenev, E.Y., Wang, Q. & Warren, W.S. Direct and cost-efficient hyperpolarization of long-lived nuclear spin states on universal (15)N2-diazirine molecular tags. Sci. Adv. 2, e1501438 (2016).
Figures
SABRE-SHEATH mechanism and experimental setup.
A) SABRE-SHEATH polarization transfer catalysis: Reversible exchange reactions lead to continuous pumping of hyperpolarization onto the substrate.
B) magnetic shields employed to establish the mG magnetic fields.
Coherent control of SABRE-SHEATH spin dynamics
A) The pulse sequence. The low 5 mG field enables polarization transfer. The higher field stops spin evolution, stores created hyperpolarization and allows for parahydrogen recharge on the PTC.
B) Optimization of τp with constant τd =300 ms.
C) Optimization of τd with constant τp =22 ms.