Hyperpolarized Pyruvate (13C) Injection, containing spin-polarized (“hyperpolarized”) [13C]pyruvate, is being studied as a diagnostic agent in combination with 13C spectroscopic MR imaging. The aim is to visualize [13C]pyruvate and its metabolites and thereby distinguish between anatomical areas with normal vs. abnormal metabolism, which should be useful in diagnosing and characterizing, for example, malignancy. Hyperpolarized Pyruvate (13C) Injection and [13C]pyruvate are general terms used throughout this brochure, that refer to all 13C labeling patterns, such as [1-13C]pyruvate, [2-13C]pyruvate and [1,2-13C]pyruvate. From biological and safety standpoints, pyruvate with each of the labeling patterns behaves identically in the human body [Koletzko et al., 1997].
Pyruvate is an important product of glycolysis and can be converted to various metabolites via three essential biochemical pathways associated with pyruvate dehydrogenase (PDH), lactate dehydrogenase (LDH) and alanine transaminase (ALT). Explicitly, [1-13C]pyruvate will be reduced by the NADH produced in the pathway to generate [1-13C]lactate, in the reaction catalyzed by the enzyme LDH undergoes transamination with glutamate to form [1-13C]alanine, in the reaction catalyzed by the enzyme ALT and involves the irreversible decarboxylation of [1- 13C]pyruvate to hyperpolarized [13C]CO2 in the reaction catalyzed by the mitochondrial enzyme PDH. The [13C]carbon dioxide released is subsequently interconverted with [13C]bicarbonate in the reaction catalyzed by carbonic anhydrase. These metabolites can be readily detected by 13C MRS and 13C MRI. Thus, hyperpolarized [1-13]C pyruvate has the potential to assess the flux through these metabolic pathways, which normally reflect the metabolic status of diseased tissues and their therapeutic responses to treatment.
In healthy tissues, pyruvate is preferentially converted in the mitochondria to acetyl-CoA and carbon dioxide via PDH. This is followed by entrance into the tricarboxylic acid (TCA) cycle to eventually provide cellular energy as ATP, known as oxidative phosphorylation (OXPHOS) in the mitochondria. The conversion to alanine via ALT is known to be predominant in certain healthy tissues such as liver and sometimes muscle. These preferring pathways are highly dynamic that they are readily altered under perturbations of therapeutic stress and/or tissue microenvironment conditions. As an example, without oxygen, or if the TCA cycle is running at full capacity, healthy tissue is forced to maintain energy needs through an alternate pathway that converts pyruvate to lactate via LDH and oxidizes NADH to NAD+. The NAD+ is then available to aid in further glycolytic conversion of glucose to pyruvate, providing cellular energy as ATP.
In diseased tissues, the metabolism of pyruvate is likely to be shifted away from its normal flux patterns. In oncology, most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, known as aerobic glycolysis, or the Warburg effect, rather than a comparatively low rate of glycolysis followed OXPHOS in the mitochondria. Some cancer cells also show changes in transaminase activity, suggesting pyruvate-to-alanine exchange may be enhanced or suppressed, depending on tumor type. In heart, the cardiac metabolism switches rapidly among a wide variety of substrates to supply acetyl-CoA, which typically involves four groups of reactions, or pathways to support this process: β-oxidation, glycolysis, the pentose phosphate pathway and the citric acid cycle. The PDH enzyme complex is a fundamental determinant of the relative contributions of glucose and fatty acid oxidation to ATP production in the heart, and its activity is correlated with the status of the heart disease such as myocardial ischemia (MI), diabetic cardiomyopathy, etc. This metabolic shift also occurs in many other diseases, i.e., an increase of lactic acid in inflammatory arthritis and ischemic tissues due to increase energy demands an elevated hepatic ALT activity in liver diseases. Also, the metabolic status can be a marker for the functions of certain organs, i.e., an elevated increased oxidative phosphorylation occurs in brown adipose tissue; metabolic status of placenta reflecting its role in mediating interactions & nutrient transport between mother and fetus. The metabolism of pyruvate in diseased tissues can be altered substantially via various therapeutic treatments, including modulation of major signaling pathways such as PI3K/Akt/mTOR, MEK, VEGFR, KRas, Myc, p53, etc., inhibition of metabolic pathways for PDH, LDH, HK2, GLS1 etc., immunotherapy, radiation therapy and chemotherapy.