Comparative Evaluation of Hyperpolarized [ ¹³ C]pyruvate and [ ¹³ C]lactate for Imaging Neuronal and Glioma Metabolism

Glucose and lactate are primary substrates in cerebral energy metabolism. Hyperpolarized [1-¹³C]pyruvate has become a powerful imaging agent for metabolic neuroimaging due to its central role in glucose and lactate metabolism, ability to cross the blood-brain barrier, and translational utility in neurological disorders. In particular, [1-¹³C]pyruvate enables an assessment of mitochondrial metabolism in the cerebral cortex through its conversion to [¹³C]bicarbonate. While it is not yet confirmed that production of [¹³C]bicarbonate primarily reflects neuronal metabolism, the higher affinity of neuronal transporters for lactate over pyruvate has motivated interest in hyperpolarized lactate as a more physiologic probe of neuronal metabolism. Here, we identify the predominant cellular source of [¹³C]bicarbonate and evaluate [1-¹³C]lactate as an imaging agent for neuronal metabolic imaging. <i>Ex vivo</i> NMR and mass spectrometry imaging of brain tissue collected after bolus injection of [U-¹³C₃]pyruvate revealed that pyruvate dehydrogenase dominates pyruvate carboxylase in the cortex, supporting the neuronal origin of [¹³C]bicarbonate production. Although the bicarbonate fraction among the total ¹³C products <i>in vivo</i> was higher following hyperpolarized [1-¹³C]lactate injection, the signal sensitivity was markedly reduced due to lactate's shorter T₁ and larger endogenous pool. Isotopomer analysis of brain tissue harvested 2 min after injection of [U-¹³C₃]pyruvate or [U-¹³C₃]lactate showed comparable labeling of mitochondrial intermediates. In glioma-bearing rats, <i>in vivo</i> imaging revealed an elevated pyruvate-to-lactate ratio within the tumor, highlighting altered redox and transport dynamics in malignancy. These findings demonstrate that both hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate can effectively probe neuronal and glioma metabolism, although pyruvate outperforms lactate in detecting pyruvate dehydrogenase flux.