Imaging Hyperpolarized Pyruvate and Lactate after Blood-Brain Barrier Disruption with Focused Ultrasound

Imaging of hyperpolarized ¹³C-labeled substrates has emerged as an important magnetic resonance (MR) technique to study metabolic pathways in real time in vivo. Even though this technique has found its way to clinical trials, in vivo dynamic nuclear polarization is still mostly applied in preclinical models. Its tremendous increase in signal-to-noise ratio (SNR) overcomes the intrinsically low MR sensitivity of the ¹³C nucleus and allows real-time metabolic imaging in small structures like the mouse brain. However, applications in brain research are limited as delivery of hyperpolarized compounds is restrained by the blood-brain barrier (BBB). A local noninvasive disruption of the BBB could facilitate delivery of hyperpolarized substrates and create opportunities to study metabolic pathways in the brain that are generally not within reach. In this work, we designed a setup to apply BBB disruption in the mouse brain by MR-guided focused ultrasound (FUS) prior to MR imaging of ¹³C-enriched hyperpolarized [1-¹³C]-pyruvate and its conversion to [1-¹³C]-lactate. To overcome partial volume issues, we optimized a fast multigradient-echo imaging method (temporal resolution of 2.4 s) with an in-plane spatial resolution of 1.6 × 1.6 mm², without the need of processing large amounts of spectroscopic data. We demonstrated the feasibility to apply ¹³C imaging in less than 1 h after FUS treatment and showed a locally disrupted BBB during the time window of the whole experiment. From detected hyperpolarized pyruvate and lactate signals in both FUS-treated and untreated mice, we conclude that even at high spatial resolution, signals from the blood compartment dominate in the ¹³C images, leaving the interpretation of hyperpolarized signals in the mouse brain challenging.