[6,6′‐ ²H ₂] 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′‐ ²H ₂] 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′‐ ²H ₂] 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.