A major challenge in cancer biology is to monitor and understand cancer metabolism in vivo with the goal of improved diagnosis and perhaps therapy. Because of the complexity of biochemical pathways, tracer methods are required for detecting specific enzyme-catalyzed reactions. Stable isotopes such as (13)C or (15)N with detection by nuclear magnetic resonance provide the necessary information about tissue biochemistry, but the crucial metabolites are present in low concentration and therefore are beyond the detection threshold of traditional magnetic resonance methods. A solution is to improve sensitivity by a factor of 10,000 or more by temporarily redistributing the populations of nuclear spins in a magnetic field, a process termed hyperpolarization. Although this effect is short-lived, hyperpolarized molecules can be generated in an aqueous solution and infused in vivo where metabolism generates products that can be imaged. This discovery lifts the primary constraint on magnetic resonance imaging for monitoring metabolism-poor sensitivity-while preserving the advantage of biochemical information. The purpose of this report was to briefly summarize the known abnormalities in cancer metabolism, the value and limitations of current imaging methods for metabolism, and the principles of hyperpolarization. Recent preclinical applications are described. Hyperpolarization technology is still in its infancy, and current polarizer equipment and methods are suboptimal. Nevertheless, there are no fundamental barriers to rapid translation of this exciting technology to clinical research and perhaps clinical care.

Current experimental and theoretical progress toward the goal of controlling quantum dynamics is summarized. Two key developments have now revitalized the field. First, appropriate ultrafast laser pulse shaping capabilities have only recently become practical. Second, the introduction of engineering control concepts has put the required theoretical framework on a rigorous foundation. Extrapolations to determine what is realistically possible are presented.

Parahydrogen is demonstrated to efficiently transfer its nuclear spin hyperpolarization to nitrogen-15 in pyridine and nicotinamide (vitamin B3 amide) by conducting “signal amplification by reversible exchange” (SABRE) at microtesla fields within a magnetic shield. Following transfer of the sample from the magnetic shield chamber to a conventional NMR spectrometer, the 15N NMR signals for these molecules are enhanced by ∼30,000- and ∼20,000-fold at 9.4 T, corresponding to ∼10% and ∼7% nuclear spin polarization, respectively. This method, dubbed “SABRE in shield enables alignment transfer to heteronuclei” or “SABRE-SHEATH”, promises to be a simple, cost-effective way to hyperpolarize heteronuclei. It may be particularly useful for in vivo applications because of longer hyperpolarization lifetimes, lack of background signal, and facile chemical-shift discrimination of different species.

NMR signal amplification by reversible exchange (SABRE) is a NMR hyperpolarization technique that enables nuclear spin polarization enhancement of molecules via concurrent chemical exchange of a target substrate and parahydrogen (the source of spin order) on an iridium catalyst. Recently, we demonstrated that conducting SABRE in microtesla fields provided by a magnetic shield enables up to 10% 15N-polarization (Theis, T.; et al. J. Am. Chem. Soc.2015, 137, 1404). Hyperpolarization on 15N (and heteronuclei in general) may be advantageous because of the long-lived nature of the hyperpolarization on 15N relative to the short-lived hyperpolarization of protons conventionally hyperpolarized by SABRE, in addition to wider chemical shift dispersion and absence of background signal. Here we show that these unprecedented polarization levels enable 15N magnetic resonance imaging. We also present a theoretical model for the hyperpolarization transfer to heteronuclei, and detail key parameters that should be optimized for efficient 15N-hyperpolarization. The effects of parahydrogen pressure, flow rate, sample temperature, catalyst-to-substrate ratio, relaxation time (T1), and reversible oxygen quenching are studied on a test system of 15N-pyridine in methanol-d4. Moreover, we demonstrate the first proof-of-principle 13C-hyperpolarization using this method. This simple hyperpolarization scheme only requires access to parahydrogen and a magnetic shield, and it provides large enough signal gains to enable one of the first 15N images (2 × 2 mm2 resolution). Importantly, this method enables hyperpolarization of molecular sites with NMR T1 relaxation times suitable for biomedical imaging and spectroscopy.

Intermolecular multiple-quantum coherences between bulk water and a glycoprotein fragment at modest concentration (20 mM) have been experimentally produced and detected, although such coherences are inconceivable in the normal theoretical framework of nuclear magnetic resonance. A density matrix treatment explains these results by including the long-range dipolar interaction between spins and by discarding the high-temperature approximation. These results imply that peak intensities (critical for structural determinations) can be distorted in many gradient experiments, and show that magic-angle gradients provide substantial improvements with reduced gradient strengths. They also suggest methods for contrast enhancement in magnetic resonance imaging.