Metabolic Imaging in the Anesthetized Rat Brain Using Hyperpolarized [1-(13)C] Pyruvate and [1-(13)C] Ethyl Pyruvate

Abstract

Formulation, polarization, and dissolution conditions were developed to obtain a stable hyperpolarized solution of [1-¹³C]-ethyl pyruvate. A maximum tolerated concentration and injection rate were determined, and ¹³C spectroscopic imaging was used to compare the uptake of hyperpolarized [1-¹³C]-ethyl pyruvate relative to hyperpolarized [1-¹³C]-pyruvate into anesthetized rat brain. Hyperpolarized [1-¹³C]-ethyl pyruvate and [1-¹³C]-pyruvate metabolic imaging in normal brain is demonstrated and quantified in this feasibility and range-finding study. Magn Reson Med 63:1137–1143, 2010. © 2010 Wiley-Liss, Inc.

MR metabolic imaging of hyperpolarized [1-¹³C]-pyruvate has proven to be useful, especially in oncology and cardiology. Dynamic and tissue level changes in [1-¹³C]-pyruvate and its metabolic products, [1-¹³C]-lactate, [1-¹³C]-alanine, and [¹³C] bicarbonate, have been shown to correlate with metabolic states of interest, including disease progression and response to therapy. However, for potential neurologic applications, the blood-brain transport of pyruvate may be a limiting factor. Age, anesthesia, and dietary state can all impact transport rates, and under some conditions, the 1- to 2-min window of useful hyperpolarized [1-¹³C]-pyruvate lifetime in vivo may not be sufficient. The brain uptake index (a measure of metabolite in brain versus blood), as reported for pyruvate in normal anesthetized rat brain 10 sec after an arterial injection, suggests that even at the very highest intravascular doses possible, less than 1 mM pyruvate would be transported into brain tissue. An alternative approach is the use of ethyl pyruvate (EP), a lipophilic analog of pyruvate that is expected to have faster transport across the blood-brain barrier. EP is a food additive and has been studied as an anti-inflammatory compound with therapeutic potential. Biologic and therapeutic differences between EP and pyruvate are not fully understood. EP has been shown to attenuate kainic acid–induced neuronal cell death in the mouse hippocampus and reduce the impact of stroke. Under conditions of slow intravenous infusion, EP is tolerated in large doses in both animals and humans. In this initial study, we explore the feasibility of polarizing a stable formulation of [1-¹³C]-EP and compare spectroscopic images of uptake and metabolism in normal anesthetized rat brain relative to the uptake and metabolism of hyperpolarized [1-¹³C]-pyruvate.