Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development

Hou, Lu; Rong, Jian; Haider, Ahmed; Ogasawara, Daisuke; Varlow, Cassis; Schafroth, Michael A.; Mu, Linjing; Gan, Jiefeng; Xu, Hao; Fowler, Christopher J.; Zhang, Ming‐Rong; Vasdev, Neil; Ametamey, Simon M.; Cravatt, Benjamin F.; Wang, Lu; Liang, Steven H.

doi:10.1021/acs.jmedchem.0c01459

Cited by 39 publications

(50 citation statements)

References 246 publications

(413 reference statements)

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“…Despite tremendous efforts, the development of a suitable radiotracer for PET imaging of the CB2R in the brain remains a challenging task [ 47 ]. To gain eligibility for consideration as a potential PET radioligand for brain imaging, the first criterion to be fulfilled by a CB2R ligand is high receptor affinity and selectivity, which in many cases is hampered by the homologous similarity between CB1R and CB2R.…”

Section: Introductionmentioning

confidence: 99%

“…The development of CB2R ligands with optimal lipophilicity as a brain-targeting drug is also challenging due to the highly lipophilic nature of the CB2R binding pocket and its ability to primarily recognise highly lipophilic compounds (e.g., THC has a LogD 7.4 > 7) [ 48 , 49 ]. Figure 1 shows some of the most representative CB2R radioligands [ 42 , 47 ]. Among them, [ 11 C] NE40 [ 50 , 51 ] is the only CB2R radioligand investigated in humans so far [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

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Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

Teodoro

Gündel

Deuther‐Conrad

et al. 2021

IJMS

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Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

Teodoro

Gündel

Deuther‐Conrad

et al. 2021

IJMS

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“…Recently, several studies for NHP brain imaging using PET radioligands for MAGL were reported using [20], 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 [21]. Compared to these PET radioligands, [ 11 C]PF-06809247 showed similar or higher brain uptake (4 SUV at peak) with clear blocking effect by a de ned MAGL inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Target Occupancy Study and Whole-Body Dosimetry with a MAGL PET Ligand 11C-PF-06809247 in non-human Primates

Arakawa

Takano

Nag

et al. 2021

Preprint

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BackgroundMonoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system (CNS). To develop [11C]PF-06809247 into a clinically usable positron emission tomography (PET) radioligand, we assessed the brain target occupancy of a MAGL inhibitor using non-human primate (NHP). Additionally, we measured the whole-body distribution of [11C]PF-06809247 in NHP and estimated human effective radiation doses.MethodsSeven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a selective MAGL inhibitor, (total of seven doses between 0.01-1.27 mg/kg). Kinetic parameters K1, k2 and k3 were estimated by an irreversible two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. Ki by 2TC and Patlak analysis were calculated. 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.ResultsRadioactivity 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 uptake values in the liver, small intestine, kidney, and brain. The effective dose was calculated as 4.3 μSv/MBq.Conclusions[11C]PF-06809247 is a promising PET ligand for further MAGL studies in human brain.

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“…The endocannabinoid system (eCS) is a retrograde modulating system for the homeostasis of neurotransmitters in emergency conditions such as ischemia 4 , 5 . The eCS incorporates the endocannabinoids (eCBs), their synthetic and degradative enzymes, eCB transporters, and cannabinoid receptors (CB1 and CB2).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of minocycline and KML29, a potent inhibitor of monoacylglycerol lipase, in an experimental stroke model: a small-animal positron emission tomography study

et al. 2021

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Hypoxia caused by ischemia induces acidosis and neuroexcitotoxicity, resulting in neuronal death in the central nervous system (CNS). Monoacylglycerol lipase (MAGL) is a modulator of 2-arachidonoylglycerol (2-AG), which is involved in retrograde inhibition of glutamate release in the endocannabinoid system. In the present study, we used positron emission tomography (PET) to monitor MAGL-positive neurons and neuroinflammation in the brains of ischemic rats. Additionally, we performed PET imaging to evaluate the neuroprotective effects of an MAGL inhibitor in an ischemic injury model. Methods: Ischemic-injury rat models were induced by intraluminal right middle cerebral artery occlusion (MCAO). PET studies of the brains of the ischemic rats were performed at several experimental time points (pre-occlusion, days 2, 4, and 7 after the MCAO surgery) using [ 11 C]SAR127303 for MAGL and [ 18 F]FEBMP for 18 kDa translocator protein (TSPO, a hall-mark of neuroinflammation). Medication using minocycline (a well-known neuroprotective agent) or KML29 (a potent MAGL inhibitor) was given immediately after the MCAO surgery and then daily over the subsequent three days. Results: PET imaging of the ischemic rats using [ 11 C]SAR127303 showed an acute decline of radioactive accumulation in the ipsilateral side at two days after MCAO surgery (ratio of the area under the curve between the ipsilateral and contralateral sides: 0.49 ± 0.04 in the cortex and 0.73 ± 0.02 in the striatum). PET imaging with [ 18 F]FEBMP, however, showed a moderate increase in accumulation of radioactivity in the ipsilateral hemisphere on day 2 (1.36 ± 0.11), and further increases on day 4 (1.72 ± 0.15) and day 7 (1.99 ± 0.06). Treatment with minocycline or KML29 eased the decline in radioactive accumulation of [ 11 C]SAR127303 for MAGL (minocycline-treated group: 0.82 ± 0.06 in the cortex and 0.81 ± 0.05 in the striatum; KML29-treated group: 0.72 ± 0.07 in the cortex and 0.88 ± 0.04 in the striatum) and increased uptake of [ 18 F]FEBMP for TSPO (minocycline-treated group: 1.52 ± 0.21 in the cortex and 1.56 ± 0.11 in the striatum; KML29-treated group: 1.63 ± 0.09 in the cortex and 1.50 ± 0.17 in the striatum). In MCAO rats, minocycline treatment showed a neuroprotective effect in the sensorimotor cortex suffering from severe hypoxic injury, whereas KML29 treatment saved neurons in the striatum, including bundles of myelinated axons. Conclusions: PET imaging allowed visualization of the different neuroprotective effects of minocycline and KML29, and indicated that combination pharmacotherapy using these drugs may be an effective therapy in acute ischemia.

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Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development

Cited by 39 publications

References 246 publications

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

Target Occupancy Study and Whole-Body Dosimetry with a MAGL PET Ligand 11C-PF-06809247 in non-human Primates

Neuroprotective effects of minocycline and KML29, a potent inhibitor of monoacylglycerol lipase, in an experimental stroke model: a small-animal positron emission tomography study

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