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- 13 C]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- 13 C]pyruvate enables an assessment of mitochondrial metabolism in the cerebral cortex through its conversion to [ 13 C]bicarbonate. While it is not yet confirmed that production of [ 13 C]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 [ 13 C]bicarbonate and evaluate [1- 13 C]lactate as an imaging agent for neuronal metabolic imaging. Ex vivo NMR and mass spectrometry imaging of brain tissue collected after bolus injection of [U– 13 C 3 ]pyruvate revealed that pyruvate dehydrogenase dominates pyruvate carboxylase in the cortex, supporting the neuronal origin of [ 13 C]bicarbonate production. Although the bicarbonate fraction among the total 13 C products in vivo was higher following hyperpolarized [1- 13 C]lactate injection, the signal sensitivity was markedly reduced due to lactate’s shorter T 1 and larger endogenous pool. Isotopomer analysis of brain tissue harvested 2 min after injection of [U– 13 C 3 ]pyruvate or [U– 13 C 3 ]lactate showed comparable labeling of mitochondrial intermediates. In glioma-bearing rats, in vivo 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- 13 C]pyruvate and [1- 13 C]lactate can effectively probe neuronal and glioma metabolism, although pyruvate outperforms lactate in detecting pyruvate dehydrogenase flux.