Potential for in vivo visualization of intracellular pH gradient in the brain using PET imaging.
Autor: | Yamasaki T; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Mori W; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Ohkubo T; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.; SHI Accelerator Service Co. Ltd., Tokyo 141-0031, Japan., Hiraishi A; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Zhang Y; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Kurihara Y; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.; SHI Accelerator Service Co. Ltd., Tokyo 141-0031, Japan., Nengaki N; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.; SHI Accelerator Service Co. Ltd., Tokyo 141-0031, Japan., Tashima H; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Fujinaga M; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan., Zhang MR; Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan. |
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Jazyk: | angličtina |
Zdroj: | Brain communications [Brain Commun] 2024 May 22; Vol. 6 (3), pp. fcae172. Date of Electronic Publication: 2024 May 22 (Print Publication: 2024). |
DOI: | 10.1093/braincomms/fcae172 |
Abstrakt: | Intracellular pH is a valuable index for predicting neuronal damage and injury. However, no PET probe is currently available for monitoring intracellular pH in vivo . In this study, we developed a new approach for visualizing the hydrolysis rate of monoacylglycerol lipase, which is widely distributed in neurons and astrocytes throughout the brain. This approach uses PET with the new radioprobe [ 11 C]QST-0837 (1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-phenyl-1 H -pyrazol-3-yl)azetidine-1-[ 11 C]carboxylate), a covalent inhibitor containing an azetidine carbamate skeleton for monoacylglycerol lipase. The uptake and residence of this new radioprobe depends on the intracellular pH gradient, and we evaluated this with in silico , in vitro and in vivo assessments. Molecular dynamics simulations predicted that because the azetidine carbamate moiety is close to that of water molecules, the compound containing azetidine carbamate would be more easily hydrolyzed following binding to monoacylglycerol lipase than would its analogue containing a piperidine carbamate skeleton. Interestingly, it was difficult for monoacylglycerol lipase to hydrolyze the azetidine carbamate compound under weakly acidic (pH 6) conditions because of a change in the interactions with water molecules on the carbamate moiety of their complex. Subsequently, an in vitro assessment using rat brain homogenate to confirm the molecular dynamics simulation-predicted behaviour of the azetidine carbamate compound showed that [ 11 C]QST-0837 reacted with monoacylglycerol lipase to yield an [ 11 C]complex, which was hydrolyzed to liberate 11 CO Competing Interests: The authors report no competing interests. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.) |
Databáze: | MEDLINE |
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