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bioRxiv · 10.1101/2023.06.21.546029

In vivo visualization of intracellular pH gradient in brain using PET imaging

Yamasaki, T.·Mori, W.·Ohkubo, T.·Hiraishi, A.·Zhang, Y.·Kurihara, Y.·Nengaki, N.·Tashima, H.·Fujinaga, M.·Zhang, M.-R.
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Abstract

Intracellular pH (pHi) is a valuable index for predicting hypoxic brain damage. However, no positron emission tomography (PET) probe is currently available for monitoring pHi in vivo. In this study, we developed a new approach for visualizing monoacylglycerol lipase (MAGL) activity in the brain. This approach used PET with a new probe [11C]HC-A, an azetidine carbamate inhibitor, whose uptake and residence depended on the pHi gradient was evaluated with in silico, in vitro, and in vivo assessments. Molecular dynamics simulations predicted that complex (complex-A) between HC-A and MAGL would be difficult to hydrolyze under acidic conditions. In vitro assessment using rat brain homogenate showed that [11C]HC-A reacted with MAGL to yield [11C]complex-A, which was rapidly hydrolyzed to liberate 11CO2. The 11CO2 liberation rate was slower at lower pH. In PET with [11C]HC-A using ischemic rats, the radioactivity clearance rate, which reflects the production rate of 11CO2 in the brain, was lower in a remarkably hypoxic area than in the contralateral region. In conclusion, we successfully visualized the pHi gradient in the brain using PET imaging.

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Yamasaki, T., Mori, W., Ohkubo, T., Hiraishi, A., Zhang, Y., Kurihara, Y., Nengaki, N., Tashima, H., Fujinaga, M., Zhang, M.-R.. 2023-06-24. In vivo visualization of intracellular pH gradient in brain using PET imaging. https://doi.org/10.1101/2023.06.21.546029

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