Demonstration of intracellular pH-weighting PET imaging using a new-type PET probe responsible for monoacylglycerol lipase activity in the brain

• Main Authors: Tomoteru Yamasaki, Wakana Mori, Ohkubo Takayuki, Atsuto Hiraishi, Kurihara Yusuke, Nobuki Nengaki, Zhang Ming-Rong
• Format: Conference Object
• Language: English
• Published: Elsevier Ltd. 2022
• Subjects: Carbonic acid
• Online Access: https://repo.qst.go.jp/?action=repository_uri&item_id=86458; http://id.nii.ac.jp/1657/00086439/

Objectives: The brain acidosis is caused by intracellular hyper-accumulation of acidic sources (H+, lactate, and carbonic acid) by switching the cellular energy metabolism from aerobic to anaerobic by the hypoxia. Such intra cellular acidosis give curucial injury to central nurves system of the brain. Therefore, monitoring intracellular pH would be very important to diagnosis neuronal condition. Recently, covalent inhibitors for monoacylglycerol lipase (MAGL), an enzyme intracellur lacated on neuron and astrocyte in the brain and regulates endocannabinoid system, were identified by Bulter et al [1]. Among these inhibitors, 1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-phenyl-1H-pyrazol-3-yl)azetidine-1-carboxylate (1) showed reversible inhibitory effect to MAGL. The purpose of this study is to establish quantification method of hydrolysis rate of compound 1 mediated by MAGL and to demonstrate pH-weighted PET imaging in the brain of ischemic rat.Methods: To estimate interaction between compound 1 and MAGL, docking simulations were conducted comparing to similar chemical structural irreversible-type inhibitor (2). In addition, to evaluate influents of pH shifts, molecular dynamics (MD) simulations of compound 1 were also performed under the neutral (pH 7) or acidic (pH 6) conditions. Radiosynthesis of [11C]1 and [11C]2 was described in another presentation in this meeting (Mori W, et a1.). To confirm MAGL-hydrolysis of [11C]1, in vitro assessments using rat brain homogenates were conducted. PET imaging with [11C]1 was carried out using middle cerebral artery occlusion (MCAO) rat as an acute hypoxia model and hydrolysis rate (KH) of [11C]1 with MAGL was estimated by monoexponential fitting on time-activity curves of ipsilateral region.Results: MD simulations predicted that azetidine carbamate moiety of 1 was easily hydrolyzed by MAGL due to close distance from water molecule, compared to 2 containing piperidine carbamate. Moreover, the acylated azetidine in 1 has been shown to react differently than piperidine ring size ...