Nuclear Spin Hyperpolarization
Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are extremely powerful analytical tools used to study the structure and dynamics of materials and living species. However, due to the weak interaction of nuclear magnetic moments with the applied magnetic field (less than 0.2 J/mol), NMR/MRI signals are very low. For example, even in the magnetic fields that thousands of times larger than the Earth’s magnetic field, there is only a net alignment of approximately 1 out of 100,000 nuclear spins. This means that the nuclear spin polarization (%P) is equal to only about 0.001% out of the theoretically possible 100%. This is a problem since it makes NMR acquisition times rather long, limits spatial and temporal resolution in MRI. Luckily for us, there is a way to overcome this issue — hyperpolarization. Hyperpolarization of nuclear spins means the creation of highly polarized (or highly magnetized) media. Instead of 0.001%, all of the nuclear spins can be aligned. Even if it is “only” 10% – it is still much better than 0.001%! So, how can one do that?
Hyperpolarization of nuclear spins means the creation of highly polarized (or highly magnetized) media.
There are many ways to “hyperpolarize” nuclei. Among the most widely used techniques are spin-exchange optical pumping (SEOP) of noble gases, dynamic nuclear polarization (DNP), chemically-induced dynamic nuclear polarization (CIDNP), parahydrogen-induced polarization (PHIP) and signal amplification by reversible exchange (SABRE). The last two techniques are of my particular interest because they are based on chemical interactions. And chemistry is a lot of fun! 😉
Ability to create hyperpolarized molecules presents the field of medical imaging with an amazing opportunity to improve our understanding of metabolism. Currently, numerous clinical trials aim to investigate how metabolites are chemically modified inside our bodies; now this can be studied non-invasively. However, not only biomedicine can benefit from the development of hyperpolarization technologies. Hyperpolarized MRI can bring new, previously unused applications of the magnetic resonance. Indeed, when nuclei are hyperpolarized, high magnetic fields are no longer needed and the same information can be obtained in the presence of very low fields (or even in the zero magnetic field).
Parahydrogen-induced Polarization (PHIP)
In 1986 Bowers and Weitekamp proposed a method for achieving very high nuclear polarizations using parahydrogen. Parahydrogen (para-H2) is a nuclear spin isomer of hydrogen molecule with total angular momentum 𝐼 = 0. Though para-H2 itself is NMR-silent (since it has no net magnetic moment), it carries singlet nuclear spin order which may be transformed to observable magnetization by various mechanisms. PHIP employs hydrogenation as such a mechanism. Indeed, upon incorporation of a para-H2 molecule into an asymmetric molecular precursor, the symmetry of the para-H2-nascent nuclear spins becomes broken and the high spin order becomes accessible for manipulations (Figure 1). Since, fundamentally, achieved %𝑃 is not dependent on the external magnetic field and may approach 100%, PHIP can provide enhancements of NMR signals compared to the thermal for various nuclei of up to five orders of magnitude in magnetic fields of modern NMR spectrometers (and even higher enhancements in low and ultra-low magnetic fields).
Signal Amplification By Reversible Exchange (SABRE)
SABRE also uses para-H2 as a source of spin order. However, unlike PHIP, it does not require hydrogenation reaction to polarize the substrate of interest. In the SABRE effect, signal enhancement is endowed by a reversible association of para-H2 and a to-be-polarized substrate with a metal complex, allowing the transfer of nuclear spin order from parahydrogen to the substrate (Figure 2).
SABRE is typically observed for nitrogen-containing heterocycles, when a metal complex (typically referred to as the “magnetization transfer catalyst” or simply “catalyst”) is used to briefly bring hydrogen and a substrate into contact with each other and to facilitate exchange with their free forms in solution. Latest advances in SABRE allow polarizing a wide range of vitamins, metabolites, and drugs, making it a promising modality for studying metabolism in vivo by means of NMR/MRI.
Nuclear Spin Chemistry
The Interplay between Chemistry and Nuclear Spin Dynamics
Precise coherent control of the nuclear spin dynamics made NMR spectroscopy a unique tool that allowed scientists to test quantum mechanics and the basic laws of nature. However, due to the limitations imposed by molecular symmetry, some transformations of nuclear spin states are not possible. The way to overcome this problem and to expand our ability to fully manipulate spin dynamics is to involve chemical reactions.
By combining the coherent control (RF pulses, variations of the magnetic field, etc.) with the ability to govern the incoherent dynamics (e.g., adding the catalysts/inhibitors to facilitate/suppress chemical reactions), one will be able to unlock the full potential of nuclear spin dynamics and will be able to create nuclear spin states that have not considered to be accessible before.
Long-lived Spin States
Long-lived spin states are the example of our ability to take advantage of interesting quantum-mechanical properties of nuclear spins. The most common example of a long-lived state is given by the singlet state of two spins. Such a state, αβ–βα, is immune to dipolar relaxation, which is often the dominant relaxation mechanism in liquid-state NMR. In other words, two spins “don’t see each other” if they are prepared in a singlet state. Therefore, singlet relaxation occurs much slower than T1 or T2 relaxation. Long-lived singlet order can be generated either by transferring the singlet spin order of para-H2 into the singlet spin order of a SABRE substrate or by converting net magnetization of a substrate by means of special pulse sequences. Remarkably, long-lived spin states can exist even in more complicated nuclear spin systems (containing more than 2 spins) if a molecule possesses certain symmetry requirements. Long-lived spin states coupled with hyperpolarization can be used to study metabolomic processes that occur on a timescale of several minutes or even hours, therefore, significantly extending our ability to study biochemistry by MRI.
Quantum indistinguishability in chemical reactions
Quantum indistinguishability is an important phenomenon that is crucial for understanding many physical experiments. However, it is typically ignored in chemistry. For example, while in most simulations electrons are treated quantum mechanically, the much heavier ions are treated as distinguishable and classical. Moreover, in chemical reactions of molecules in solution, nuclear spins are generally believed to play little role, despite their long quantum coherence times. Recent theoretical work demonstrated the existence of a direct connection between nuclear spins and their effect of chemical reaction rates showing that, in many situations, a full quantum treatment of collective nuclear degrees of freedom is essential. Experimental demonstration of this phenomenon for chemical reactions in solution has not been carried out. Any reaction that can be manipulated by controlling nuclear spins represents a unique platform for testing fundamental laws of nature as well as opportunities for new applications. Indeed, would not it be great to control chemical reactions by simply manipulating magnetic or radiofrequency fields?