T₂relaxation times of¹³C metabolites in a rat hepatocellular carcinoma model measuredin vivousing¹³C-MRS of hyperpolarized [1-¹³C]pyruvate

Abstract

A single-voxel Carr-Purcell-Meibloom-Gill sequence was developed to measure localized T 2 relaxation times of 13 C-labeled metabolites in vivo for the first time. Following hyperpolarized [1-13 C]pyruvate injections, pyruvate and its metabolic products, alanine and lactate, were observed in the liver of five rats with hepatocellular carcinoma and five healthy control rats. The T 2 relaxation times of alanine and lactate were both significantly longer in HCC tumors than in normal livers (p < 0.002). The HCC tumors also showed significantly higher alanine signal relative to the total 13 C signal than normal livers (p < 0.006). The intra-and inter-subject variations of the alanine T 2 relaxation time were 11% and 13%, respectively. The intra-and inter-subject variations of the lactate T 2 relaxation time were 6% and 7%, respectively. The intra-subject variability of alanine to total carbon ratio was 16% and the inter-subject variability 28%. The intra-subject variability of lactate to total carbon ratio was 14% and the inter-subject variability 20%. The study results show that the signal level and relaxivity of [1-13 C]alanine may be promising biomarkers for HCC tumors. Its diagnostic values in HCC staging and treatment monitoring are yet to be explored.

Tumor imaging using hyperpolarized 13C magnetic resonance spectroscopy

“…The T 2 relaxation times for both [1-13 C]pyruvate and lactate show apparent multiexponential behavior, with a very short T 2 component of $100 ms (66). The relative fractions of these components are consistent with them being from intracellular and extracellular pools, although this has not been demonstrated and care is required when interpreting data from such measurements (29). If this is the case, then by selecting signal from these different components, it may be possible to determine the relative importance of membrane transport.…”

“…There is also evidence that pyruvate-lactate exchange can be used to identify tumor grade in a transgenic adenocarcinoma of mouse prostate (TRAMP) (28), with hyperpolarized lactate levels showing a strong correlation with the histologic grade of the excised tumors. The alanine and bicarbonate labeling varies more between tumor models, possibly due to variations in relative alanine transaminase and pyruvate dehydrogenase activity (28,29,48). In particular, alterations in labeled alanine levels have been suggested as a useful marker in rat hepatocellular carcinoma (29).…”

“…The alanine and bicarbonate labeling varies more between tumor models, possibly due to variations in relative alanine transaminase and pyruvate dehydrogenase activity (28,29,48). In particular, alterations in labeled alanine levels have been suggested as a useful marker in rat hepatocellular carcinoma (29).…”

Hyperpolarized [1,3‐13C2]ethyl acetoacetate is a novel diagnostic metabolic marker of liver cancer

“…C 2 ]pyruvate in the same animal model, showing the amount of pyruvate collected within the tumor to be on average twice the level of pyruvate in healthy liver 24 (Supporting Information S3). Gd-DCE-MRI data instead cannot be used to consistently back up the observation, due to the different physical-chemical properties (size, lipophilicity, etc.)…”

Alternating Acquisition Technique for Quantification of in vitro Hyperpolarized [1-13C] Pyruvate Metabolism

“…Hyperpolarized 13 C MRS studies were primarily focused on utilizing lactate dehydrogenase (LDH)-catalyzed 13 C label exchange between injected hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C] pyruvate and [1][2][3][4][5][6][7][8][9][10][11][12][13] C] lactate and also [1][2][3][4][5][6][7][8][9][10][11][12][13] C] alanine via alanine aminotransferase (14). Some research also investigated quantifying and modeling these metabolic processes, and has shown that conserving the hyperpolarized magnetization of the substrate and increasing the metabolic product peak signal to noise ratio (PSNR) can potentially benefit accurate kinetic modeling (15)(16)(17)(18)(19). This is especially important for in vitro experiments since cell number counts are likely to be limited relative to the in vivo case.…”