Friday, September 18, 2015

Hyperpolarized [ C]ketobutyrate, a molecular analog of pyruvate with modified specificity for LDH isoforms


von Morze, C., et al., Hyperpolarized [ C]ketobutyrate, a molecular analog of pyruvate with modified specificity for LDH isoforms. Magn Reson Med, 2015: p. n/a-n/a.


PURPOSE: The purpose of this study was to investigate 13 C hyperpolarization of alpha-ketobutyrate (alphaKB), an endogenous molecular analog of pyruvate, and its in vivo enzymatic conversion via lactate dehydrogenase (LDH) using localized MR spectroscopy. METHODS: Hyperpolarized (HP) 13 C MR experiments were conducted using [13 C]alphaKB with rats in vivo and with isolated LDH enzyme in vitro, along with comparative experiments using [13 C]pyruvate. Based on differences in the kinetics of its reaction with individual LDH isoforms, HP [13 C]alphaKB was investigated as a novel MR probe, with added specificity for activity of LDHB-expressed H ("heart"-type) subunits of LDH (e.g., constituents of LDH-1 isoform). RESULTS: Comparable T1 and polarization values to pyruvate were attained (T1 = 52 s at 3 tesla [T], polarization = 10%, at C1 ). MR experiments showed rapid enzymatic conversion with substantially increased specificity. Formation of product HP [13 C]alpha-hydroxybutyrate (alphaHB) from alphaKB in vivo was increased 2.7-fold in cardiac slabs relative to liver and kidney slabs. In vitro studies resulted in 5.0-fold higher product production from alphaKB with bovine heart LDH-1, as compared with pyruvate. CONCLUSIONS: HP [13 C]alphaKB may be a useful MR probe of cardiac metabolism and other applications where the role of H subunits of LDH is significant (e.g., renal cortex and brain). Magn Reson Med, 2015. (c) 2015 Wiley Periodicals, Inc.