Development of the first clinically used radiotracer [18F]T-401 for positron emission tomography imaging of monoacylglycerol lipase in brain （Monoacylglycerol lipase (MAGL)を標的としたPETトレーサー[18F]T-401の開発）

概要

The clinical cost per approved new drug has increased more than 10 times in 20 years and was estimated to be $ 1,460 million in the 2000s. In addition, the success rate of therapeutic drugs targeting disorders of the central nervous system (CNS) is low, less than 10% mainly because of the lack of animal models reflecting the pathology of CNS disease in human. An estimation of effective dose of drugs, selection of appropriate patients based on mechanism of action and efficacy prediction in short-term trials by biomarkers expected to be potential options to increase the success rates of clinical trials for CNS-targeting drugs.

Positron-emission tomography (PET) is a non-invasive imaging technology that allows quantification of physiological and pathological processes in living subjects. PET imaging could potentially provide a means to determine the occupancy of a target molecule in human brain by therapeutic inhibitors. This information obtained from in vivo PET scans can afford dose setting in clinical trials, which could lead to rational protocol design and following go/no-go decision. In addition, PET imaging could allow the patient stratification for the clinical trial and the efficacy evaluation of the drug by using the radiotracer as a diagnostic marker and a surrogate marker for efficacy, respectively. Given these factors, PET technology is expected to increase success rate of the clinical trial and save its cost. Because the above technologies require a PET radiotracer that binds a target molecule specifically, the development of radiotracers is also highly required.

Endocannabinoid neurotransmission in the central and peripheral nervous systems is dependent on cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) and their endogenous fatty acid ligands. The primary endogenous ligands for CB1 and CB2 receptors are N-arachidonoyl ethanolamine (AEA), also known as anandamide, and 2-arachidonoylglycerol (2-AG). Both regulate multiple physiological processes in CNS, including pain, inflammation, appetite, memory, and emotion. AEA and 2-AG are biosynthesized by the phospholipase-catalyzed hydroxylation of membrane phospholipids and are rapidly inactivated by enzymatic hydrolysis after exerting physiological actions through the cannabinoid receptors. The degradation of these endocannabinoids is mainly mediated by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

MAGL is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and glycerol. It is responsible for about85% of 2-AG hydrolysis. Thus, inhibition of MAGL increases 2-AG levels, leading to activation of endocannabinoid neurotransmission and consequent anti-nociceptive, anxiolytic, and anti-emetic responses. In addition, MAGL inhibition decreases arachidonic acid levels, resulting in anti-inflammatory and neuroprotection effects in the brain. Thus, MAGL could be a promising target for the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington’s disease and neuropsychiatric disorders in which the endocannabinoid system and neuroinflammation have mechanistically been implicated.

Several PET imaging agents for MAGL have been reported, and some of these compounds exhibit selectivity for MAGL and high uptake in the brains of rodents and non-human primates. However, all the agents reported bind to MAGL irreversibly, preventing quantification of binding components. Accordingly, I aimed to develop PET imaging agents that bind to MAGL selectively and reversibly.

In this thesis, I present the development of novel PET imaging agents that bind to MAGL selectively and reversibly in chapter 2 and PET studies using the optimized MAGL radiotracer, [18F]T-401, for quantification of MAGL in the brain of rhesus monkey and its occupancy by a well-known MAGL inhibitor in chapter 3.

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