[6,6′‐²H₂] fructose as a deuterium metabolic imaging probe in liver cancer

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related deaths. Imaging plays a crucial role in the early detection of HCC, although current methods are limited in their ability to characterize liver lesions. Most recently, deuterium metabolic imaging (DMI) has been demonstrated as a powerful technique for the imaging of metabolism in vivo. Here, we assess the metabolic flux of [6,6′‐2H2] fructose in cell cultures and in subcutaneous mouse models at 9.4 T. We compare these rates with the most widely used DMI probe, [6,6′‐2H2] glucose, exploring the possibility of developing 2H fructose to overcome the limitations of glucose as a novel DMI probe for detecting liver tumors. Comparison of the in vitro metabolic rates implies their similar glycolytic metabolism in the TCA cycle due to comparable production rates of 2H glutamate/glutamine (glx) for the two precursors, but overall higher glycolytic metabolism from 2H glucose because of a higher production rate of 2H lactate. In vivo kinetic studies suggest that HDO can serve as a robust reporter for the consumption of the precursors in liver tumors. As fructose is predominantly metabolized in the liver, deuterated water (HDO) produced from 2H fructose is probably less contaminated from whole‐body metabolism in comparison with glucose. Moreover, in studies of the normal liver, 2H fructose is readily converted to 2H glx, enabling the characterization of 2H fructose kinetics. This overcomes a major limitation of previous 2H glucose studies in the liver, which were unable to confidently discern metabolic flux due to overlapped signals of 2H glucose and its metabolic product, 2H glycogen. This suggests a unique role for 2H fructose metabolism in HCC and the normal liver, making it a useful approach for assessing liver‐related diseases and the progression to oncogenesis.