Nuclear Spin Hyperpolarization

Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are extremely powerful analytical tools to study structure and dynamics at macroscopic, microscopic, and molecular scales. 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 rather 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 roughly one out of one hundred thousand nuclear spins meaning nuclear spin polarization %P being equal to about 0.001%. This is definitely a problem since it makes NMR/MRI scan times rather long, limits its spatial and temporal resolution. Luckily for us, there are several ways to overcome this problem. This is called hyperpolarization, which means a creation of highly polarized or highly magnetized media. Rather than one in a one hundred thousand, how about all of the spins being aligned? Or half of them, or even 10%… It is still much better than 0.001%. So, how can you do that?

There are many ways to make nuclei hyperpolarized. 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.

Recently, dramatic improvements in our ability to image specific molecules have been demonstrated using magnetic resonance imaging (MRI) of molecules prepared by a process termed hyperpolarization. Imaging hyperpolarized nuclei presents the fields of oncology and medical imaging with an opportunity to dramatically improve our ability to identify and understand tumor tissue. In addition to the absence of ionizing radiation and convenient integration with standard MRI, imaging hyperpolarized nuclei offers the prospect of monitoring tumor metabolism essentially noninvasively. Imaging of hyperpolarized 13C-labeled substrates has attracted particular interest because, unlike any other imaging technology, the products of metabolism in a specific enzyme-catalyzed reaction may be observed based on inherent MR frequency differences.

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 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. 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 (similarly to PHIP) uses para-H2 as a source of spin order, however, 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. 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.