Hyperpolarized Carbon-13 Pyruvate Magnetic Resonance Imaging
Hyperpolarization is the nuclear spin polarization of material in a magnetic field far beyond thermal equilibrium conditions determined by the Boltzmann distribution. The signal to noise ratio (SNR) in magnetic resonance can be intensified by the application of hyperpolarization. This novel technology is advancing in the area of clinical studies by using stable isotopic labels such as carbon-13.
These non-radioactive labels can be incorporated into small molecules and can then be used to study in vivo metabolic pathways in real-time. For example, carbon-13 labelled pyruvate is becoming the gold standard when it comes to the development of hyperpolarized probes. Several preclinical models have demonstrated that hyperpolarized probes can be used in the areas of neurology and oncology. Therefore, these probes can be used in conjunction with magnetic resonance imaging (MRI) and consequently have great potential towards diagnosing a disease state in personalised medicine.
The output signals generated by MRI are weak compared to other imaging modalities. These include the imaging techniques based on acoustics, optics and emission. However, several factors can be used to increase the SNR especially by applying more powerful magnetic fields, high concentrations of spins and longer acquisition times. MRI works on the human body because of its high concentration of water and therefore an abundance of protons. These protons have a relatively higher gyromagnetic ratio.
Hyperpolarization increases the signal response in magnetic resonance by increasing spin polarisation. The objective of hyperpolarization technology is to harness the unique ability of nuclear magnetic resonance spectroscopy to distinguish chemical moieties by chemical shift and to characterise their dynamic properties in vivo.
The most abundant isotope of hydrogen is the proton which has a spin of ½ a nucleus and therefore produces observable NMR signals. Consequently, the carbon-13 isotope of carbon possesses a spin of ½ a nucleus with an associated 1.1% natural abundance. To obtain a favourable NMR signal, it would be necessary to enrich the target molecule to increase SNR further isotopically.
The degree of hyperpolarization of the molecule will be the result of the location of the NMR-active nucleus. Therefore, the position of isotopic enrichment is a factor in the properties of the hyperpolarized molecule. For example, [1-13C] pyruvate molecules contain an enriched carbon-13 in position 1 of the molecule. Accordingly, this carbon-13 label would be the target of the hyperpolarization process through the nuclear spin.
The hyperpolarized carbon-13 atom will be transformed during the in vivo metabolic pathways, and each metabolite would produce a different signal. This approach offers great potential in ADME human studies because the hyperpolarized molecules can be used in vivo studies to determine the fate of the drug substance. The drug can be administered to the patient at physiological concentrations without harmful effects.
The imaging properties of hyperpolarized molecules are a function of their relaxation properties and ease of hyperpolarization. Other factors include the safety profile in addition to biological availability and metabolism profile. Several molecules including carbon-13 labelled pyruvate have been subjected to hyperpolarization, and their associated metabolism imaged. These hyperpolarized probes include [1,4-13C2]fumarate used to evaluate cell necrosis and [U-2H, U-13C]glucose for assessment of the glycolytic and pentose phosphate pathway activities and for detecting early treatment response. In addition to 13C-labelled bicarbonate for in vivo mapping of pH including 13C-labelled urea as a marker of perfusion.