Synthesis, radio-synthesis and in vitro evaluation of terminally fluorinated derivatives of HU-210 and HU-211 as novel candidate PET tracers

Zanato, Chiara; Pelagalli, Alessia; Marwick, Katie; Piras, Monica; Dall’Angelo, Sergio; Spinaci, Andrea; Pertwee, Roger G.; Wyllie, David J. A.; Hardingham, Giles E.; Zanda, Matteo

doi:10.1039/c6ob02796b

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…On the basis of the previous research, Yamasaki et al modified 1-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1) to synthesize compound [ 11 C] 17 ( K D = 15.3 μM, log D = 3.76) and conducted PET imaging where this radiotracer demonstrated high specificity in the mouse BAT (2.8 %ID/mL). Zanato et al labeled a fluorinated tetrahydrocannabinol (THC) analog HU-210F with 18 F ([ 18 F] 18 ( K i hCB1R = 0.98 nM, K i hCB2R = 3.83 nM) as a potential imaging agent, but further biological evaluation has not been carried out. The latest CB1R imaging probe [ 18 F] 19 was reported by Chang et al by modifying DBPR211; however, the uptake of this tracer in the mouse brain was low (<1%).…”

Section: Receptor Targeting Pet Tracersmentioning

confidence: 99%

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

et al. 2020

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The endocannabinoid system (ECS) is involved in a wide range of biological functions and comprises cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Over the past 2 decades, significant advances toward developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), particularly focusing on PET neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.

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Section: Receptor Targeting Pet Tracersmentioning

confidence: 99%

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

et al. 2020

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“… , Introduction of the alkyl side chain to ketone 10 proved a formidable challenge due to steric hindrance. Initial attempts using established phosphonium ylide routes yielded no reaction even at elevated temperatures. , An extensive screening of Grignard reagents either yielded no reaction or afforded exclusively Grignard reduction product 11 . Finally, using a modified procedure for the preparation of alkyl lithiums by Punzalan, we employed, for the first time, 5-chloropentyl lithium to forge the tertiary alcohol 12 in 83% yield .…”

Section: Resultsmentioning

confidence: 99%

Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists

Kosar,

Sarott,

Sykes

et al. 2024

ACS Cent. Sci.

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We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with a tailored functional response. The present study discloses the structurebased design of cannabinoid receptor type 2 (CB 2 R) selective inverse agonists (S)-1 and (R)-1, which were derived from privileged agonist HU-308 by introduction of a phenyl group at the gem-dimethylheptyl side chain. Epimer (R)-1 exhibits high affinity for CB 2 R with K d = 39.1 nM and serves as a platform for the synthesis of a wide variety of probes. Notably, for the first time these fluorescent probes retain their inverse agonist functionality, high affinity, and selectivity for CB 2 R independent of linker and fluorophore substitution. Ligands (S)-1, (R)-1, and their derivatives act as inverse agonists in CB 2 R-mediated cAMP as well as G protein recruitment assays and do not trigger βarrestin−receptor association. Furthermore, no receptor activation was detected in live cell ERK 1/2 phosphorylation and Ca 2+ -release assays. Confocal fluorescence imaging experiments with (R)-7 (Alexa488) and (R)-9 (Alexa647) probes employing BV-2 microglial cells visualized CB 2 R expressed at endogenous levels. Finally, molecular dynamics simulations corroborate the initial docking data in which inverse agonists restrict movement of toggle switch Trp258 6.48 and thereby stabilize CB 2 R in its inactive state.

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“…Analysis of the corresponding intensity plot showed virtually identical co-localization overlap between the Alexa488 ((R)-7) and JF549i (SNAP-hCB 2 R) signals (Figure 7B). Specificity of (R)-7 for CB 2 R was further ascertained by comparison of the response elicited in rat CB 2 R isoform (rCB 2 R)-expressing AtT-20 and wild-type (WT) cells, which do not express CB 2 R. 52 AtT-20(rCB2) and AtT-20 WT cells were incubated with (R)-7 and Hoechst33342 and studied by confocal imaging. Robust Alexa488 fluorescence signal was detected at the plasma membrane of AtT-20(rCB2) cells (Figure 7C, left).…”

Section: Fluorescence Confocal Microscopy In Live Cellsmentioning

confidence: 99%

Flipping the GPCR Switch: Structure–Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists

Carreira,

Kosar,

Sarott

et al. 2023

Preprint

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We report the structure-based design of cannabinoid receptor type 2 (CB2R)-selective inverse agonists (S)-1 and (R)-1, which were derived from privileged agonist HU-308 by introduction of a phenyl group at the gem-dimethylheptyl sidechain. Epimer (R)-1 exhibits high affinity for CB2R with Kd = 39 nM and serves as a platform for the synthesis of a wide variety of probes. Notably, the fluorescent probes, for the first time, retain their inverse agonist functionality, high affinity, and selectivity for CB2R independent of linker and fluorophore substitution. Ligands (S)-1, (R)-1, and their derivatives act as inverse agonists in CB2R-mediated cAMP as well as G protein recruitment assays, and do not trigger β-arrestin–receptor association. Furthermore, no receptor activation was detected in live cell ERK1/2 phosphorylation and Ca2+-release assays. Confocal fluorescence imaging experiments with (R)-7 (Alexa488) and (R)-9 (Alexa647) probes employing BV-2 microglial cells visualized CB2R expressed at endogenous levels. Finally, molecular dynamics simulations corroborate the initial docking data in which inverse agonists restrict movement of toggle switch, Trp2586.48, and thereby stabilize CB2R in its inactive state. The present study serves as a blueprint for the rational design of GPCR ligands beyond CB2R with a tailored functional response.

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Synthesis, radio-synthesis and in vitro evaluation of terminally fluorinated derivatives of HU-210 and HU-211 as novel candidate PET tracers

Abstract: Prospective PET tracers HU-210F and HU-211F were synthesised and tested as ligands of cannabinoid (CB1 and CB2) and N-methyl d-aspartate (NMDAR) receptors.

Cited by 7 publications

References 27 publications

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

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

Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists

Flipping the GPCR Switch: Structure–Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists

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