MRSI of Hyperpolarized Substrates
Hyperpolarized 13C MRS using dynamic nuclear polarization provides a unique imaging opportunity to study reaction kinetics and enzyme activities of in vivo metabolism. In contrast to conventional in vivo MRS, hyperpolarization provides up to a 20,000x fold increased signal-to-noise ratio to enable imaging of both the injected substrate and downstream metabolic products, thereby allowing the real-time interrogation of multiple key metabolic pathways at high-spatial resolution. 13C-labled pyruvate is the most studied hyperpolarized substrate to date and has the added significance of being the only hyperpolarized substrate to date to reach clinical trials. Located at a crucial hub in the energy metabolic nexus, pyruvate can be reduced to lactate as the end product of glycolysis, amidated to produce alanine, or converted in mitochondria to form acetyl CoA and CO2 (measured with 13C-MRS as a 13C-bicarbonate peak) as the first step towards oxidative phosphorylation via the TCA cycle. Operating within the constraint of in vivo T1 relaxation rates ~40s, the primary applications of hyperpolarized 13C MRS identified to date are the study of neoplasms, cardiovascular pathologies, inflammation, and metabolic disorders.
PET and hyperpolarized MRS are best thought of as complementary rather than competing imaging modalities. The strength of PET is very high sensitivity, allowing the detection of trace amounts of agents, which do not perturb the biological systems under investigation. Current clinical scanners have a spatial resolution of about 5 mm and small animal systems achieve a 1-2 mm spatial resolution. Investigating metabolism, for example using 18FDG or 11C PET in combination with kinetic modeling tools, is possible, but the measurements are indirect. The detected photons are independent of the molecular environment of the decaying nuclei, thus it is not possible to differentiate substrate signals from those of downstream metabolic products. This, however, is the strength of MRS, as individual compounds can be distinguished based on their characteristic chemical shifts and hyperpolarization provides the spatial and temporal resolution needed to measure real-time in vivo metabolic kinetics. Metabolic imaging with hyperpolarized substrates also produces no dose of ionizing radiation and allows direct spatial co-registration with high-resolution 1H-MRI.