Synthesis and preclinical evaluation of [ 11 C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL)

Ahamed, Muneer; Attili, Bala; Veghel, Daisy van; Ooms, Maarten; Berben, Philippe; Celen, Sofie; Declercq, Lieven; Savinainen, Juha R.; Laitinen, Jarmo T.; Verbruggen, Alfons; Bormans, Guy

doi:10.1016/j.ejmech.2017.04.066

Cited by 22 publications

(23 citation statements)

References 34 publications

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“…No significant washout (ratio of SUV 3.5 min / SUV 90 min = 1.2) was observed during PET scans, which was aligned with characteristic plateaued time−activity curves of typically irreversible binding PET tracers. 40,58,61 Pretreatment with KML29 (3 mg/kg), a widely-used MAGL inhibitor, remarkably decreased the uptake of 48 in various brain regions and the whole brain uptake (~50% reduction based on area under curve, AUC), which demonstrated excellent in vivo specificity of 48 towards MAGL (Figure 6B and Figure S6). We then investigated the uptake, biodistribution and clearance of 48 by whole body distribution in mice at five time points (1, 5, 15, 30 and 60 min) after tracer injection (Figure 6C and Table S1, Supporting Information).…”

Section: Preliminary Pet Imaging Studies Of Irreversible Magl Tracer 48 ([ 11 C]8)mentioning

confidence: 92%

Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a “Tail Switching” Strategy on a Piperazinyl Azetidine Skeleton

et al. 2019

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Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions including chronic pain, inflammation, cancer and neurodegeneration. Herein we disclose a novel array of reversible and irreversible MAGL inhibitors by means of tail switching on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8, and reversible-binding compounds 17 and 37 which are amenable for radiolabeling with 11 C or 18 F. [ 11 C]8 ([ 11 C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain towards MAGL. Reversible radioligands [ 11 C]17 ([ 11 C]PAD) and [ 18 F]37 ([ 18 F]MAGL-4-11) also demonstrated excellent in vivo binding specificity towards MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography (PET) tracers with tunability in reversible and irreversible binding mechanism.

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Section: Preliminary Pet Imaging Studies Of Irreversible Magl Tracer 48 ([ 11 C]8)mentioning

confidence: 92%

Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a “Tail Switching” Strategy on a Piperazinyl Azetidine Skeleton

et al. 2019

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“…Recently, several studies for NHP brain imaging using PET radioligands for MAGL were reported using [ 11 C]MAGL-0519 [ 19 ], [ 11 C]SAR127303 [ 20 ], [ 11 C]MA-PB-1 [ 21 ], [ 18 F]T-401 [ 22 ], and [ 18 F]PF-06795071 [ 1 ]. In addition, a report highlighting the opportunities and challenges of PET imaging of the endocannabinoid system was recently published [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Target occupancy study and whole-body dosimetry with a MAGL PET ligand [11C]PF-06809247 in non-human primates

et al. 2022

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Background Monoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system. To develop [11C]PF-06809247 into a clinically usable MAGL positron emission tomography (PET) radioligand, we assessed the occupancy of MAGL by an inhibitor in the non-human primate (NHP) brain. Additionally, we measured the whole-body distribution of [11C]PF-06809247 in NHP and estimated human effective radiation doses. Methods Seven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements along with arterial blood sampling were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a pro-drug of a selective MAGL inhibitor (total of seven doses between 0.01 and 1.27 mg/kg). Kinetic parameters K1, k2 and k3 were estimated by a two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. k4 was set as 0 according to the irreversible binding of [11C]PF-06809247. Ki by 2TC and Patlak analysis were calculated as the influx constant. The target occupancy was calculated using Ki at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model. Results Radioactivity retention was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4–100.5% in a dose dependent manner. Whole-body PET showed high radioactivity uptake values in the liver, small intestine, kidney, and brain. The effective dose of [11C]PF-06809247 was calculated as 4.3 μSv/MBq. Conclusions [11C]PF-06809247 is a promising PET ligand for further studies of MAGL in the human brain.

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“…PET imaging of MAGL will allow for a deeper understanding of the dynamic nature of MAGL under pathological conditions, which is currently not well understood. In this context, several reversible and irreversible MAGL-targeted PET tracers are now available for in vivo studies (122)(123)(124)(125)(126). Additionally, peripheral and central biomarkers of target engagement and pharmacological effect (i.e.…”

Section: Advancing Magl Inhibitors For the Treatment Of Anxiety And Stress-related Disordersmentioning

confidence: 99%

2-Arachidonoylglycerol Modulation of Anxiety and Stress Adaptation: From Grass Roots to Novel Therapeutics

Bedse

Hill

Patel

2020

Biological Psychiatry

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Over the past decade there has been a surge of interest in the development of endocannabinoid (eCB)-based therapeutic approaches for the treatment of diverse neuropsychiatric conditions. Although initial preclinical and clinical development efforts focused on pharmacological inhibition of fatty-acid amide hydrolase to elevate levels of the eCB anandamide, more recent efforts have focused on inhibition of monoacylglycerol lipase (MAGL) to enhance signaling of the most abundant and efficacious eCB ligand, 2-arachidonoylglycerol (2-AG). Here we review the biochemistry and physiology of 2-AG signaling and preclinical evidence supporting a role for this system in the regulation of anxiety-related outcomes and stress adaptation. We review preclinical evidence supporting MAGL inhibition for the treatment of affective, trauma and stress-related disorders, describe the current state of MAGL inhibitor drug development, and discuss biological factors that could affect MAGL inhibitor efficacy. Issues related to the clinical advancement of MAGL inhibitors are also discussed. We are cautiously optimistic, as the field of MAGL inhibitor development transitions from preclinical to clinical and theoretical to practical, that pharmacological 2-AG augmentation could represent a mechanistically novel therapeutic approach for the treatment of affective and stress-related neuropsychiatric disorders.

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Synthesis and preclinical evaluation of [ 11 C]MA-PB-1 for in vivo imaging of brain monoacylglycerol lipase (MAGL)

Cited by 22 publications

References 34 publications

Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a “Tail Switching” Strategy on a Piperazinyl Azetidine Skeleton

Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a “Tail Switching” Strategy on a Piperazinyl Azetidine Skeleton

Target occupancy study and whole-body dosimetry with a MAGL PET ligand [11C]PF-06809247 in non-human primates

2-Arachidonoylglycerol Modulation of Anxiety and Stress Adaptation: From Grass Roots to Novel Therapeutics

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