Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold

Rong, Jian; Mori, Wakana; Xia, Xiaotian; Schafroth, Michael A.; Zhao, Chunyu; Van, Richard; Yamasaki, Tomoteru; Chen, Jiahui; Xiao, Zhiwei; Haider, Ahmed; Ogasawara, Daisuke; Hiraishi, Atsuto; Shao, Tuo; Zhang, Yiding; Chen, Zhe; Pang, Fuwen; Hu, Kuan; Xie, Lin; Fujinaga, Masayuki; Kumata, Katsushi; Gou, Yuancheng; Fang, Yuwei; Gu, Shuyin; Wei, Huiyi; Bao, Liang; Xu, Hao; Collier, Thomas Lee; Shao, Yihan; Carson, Richard E.; Cravatt, Benjamin F.; Wang, Lu; Zhang, Ming‐Rong; Liang, Steven H.

doi:10.1021/acs.jmedchem.1c00747

Cited by 9 publications

(18 citation statements)

References 56 publications

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“…In addition to that, the topological surface area of ( R )-[ 18 F] 13 is reduced (53.09 vs 68.58 from [ 18 F]T-401 in ChemDraw 19.0) and falls into the desirable range of PET design parameters according to the previous report, which may also contribute to this improved kinetic profile. Compared to [ 11 C]PAD and [ 18 F]MAGL-2102 that exhibited a slow kinetic profile with a tight-binding mechanism in rodent brains, , ( R )-[ 18 F] 13 is superior with faster clearance in analogue to its lead structure and harbors the possibility of kinetic modeling. Consequently, ( R )-[ 18 F] 13 possess favored features as a reversible MAGL PET tracer.…”

Section: Results and Discussionmentioning

confidence: 99%

“…The procedure described for the synthesis of 10 was applied to (2-fluoropyridin-3-yl)boronic acid (22.6 mg, 0.16 mmol), compound 8 (60.0 mg, 0.13 mmol), cesium carbonate (108 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (0) (12.23 mg, 0.13 mmol), and SPhos (11.0 mg, 0.26 mmol) to afford compound 22 as a white solid (21 mg, 38%). 1 (23). The procedure described for the synthesis of 10 was applied to (R)-(−)-3-fluoropyrrolidine hydrochloride (18.8 mg, 0.15 mmol), compound 8 (56.0 mg, 0.12 mmol), cesium carbonate (122 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (0) (11.4 mg, 0.13 mmol), and SPhos (10.2 mg, 0.24 mmol) to afford compound 23 as a white solid (16 mg, 32%).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…While their in vivo specificities were confirmed in peripheral MAGL-expressing organs, no specific interaction in the rat brain could be demonstrated. [ 18 F]T-401 and [ 18 F]MAGL-2102 are the recently reported reversible MAGL radioligands that showed specificity toward CNS MAGL in vivo . , However, low to moderate brain uptake was observed for [ 18 F]T-401, and a slow reversible binding mechanism was revealed for [ 18 F]MAGL-2102. Taken together, a novel MAGL PET radioligand with improved brain uptake and proper pharmacokinetics is desirable for clinical practice.…”

Section: Introductionmentioning

confidence: 99%

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Development of High Brain-Penetrant and Reversible Monoacylglycerol Lipase PET Tracers for Neuroimaging

Schild

Grether

et al. 2022

J. Med. Chem.

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Monoacylglycerol lipase (MAGL) is one of the key enzymes in the endocannabinoid system. Inhibition of MAGL has been proposed as an attractive approach for the treatment of various diseases. In this study, we designed and successfully synthesized two series of piperazinyl pyrrolidin-2-one derivatives as novel reversible MAGL inhibitors. (R)-[18F]13 was identified through the preliminary evaluation of two carbon-11-labeled racemic structures [11C]11 and [11C]16. In dynamic positron-emission tomography (PET) scans, (R)-[18F]13 showed a heterogeneous distribution and matched the MAGL expression pattern in the mouse brain. High brain uptake and brain-to-blood ratio were achieved by (R)-[18F]13 in comparison with previously reported reversible MAGL PET radiotracers. Target occupancy studies with a therapeutic MAGL inhibitor revealed a dose-dependent reduction of (R)-[18F]13 accumulation in the mouse brain. These findings indicate that (R)-[18F]13 ([18F]YH149) is a highly promising PET probe for visualizing MAGL non-invasively in vivo and holds great potential to support drug development.

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Section: Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of High Brain-Penetrant and Reversible Monoacylglycerol Lipase PET Tracers for Neuroimaging

Schild

Grether

et al. 2022

J. Med. Chem.

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“…Copper-induced nucleophilic 18 F labeling, which was developed by Gouverneur’s ( Tredwell et al, 2014 ; Taylor et al, 2017 ) and Scott’s group ( Chu and Qing, 2014 ), is another strategy for radiofluorination of a non-active aromatic ring. There is easy access to the precursor BPE via Miyaura boration ( Ishiyama et al, 1995 ), which would be complementary to SCIDY synthesis ( Rong et al, 2021 ). Because of this, we also systemically evaluated BPE radiolabeling feasibility in our FX2N module.…”

Section: Resultsmentioning

confidence: 99%

Easily automated radiosynthesis of [18F]P10A-1910 and its clinical translation to quantify phosphodiesterase 10A in human brain

Wei

Zhang

et al. 2022

Front. Bioeng. Biotechnol.

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Our previous work showed that [18F]P10A-1910 was a potential radioligand for use in imaging phosphodiesterase 10A (PDE10A). Specifically, it had high brain penetration and specific binding that was demonstrated in both rodents and non-human primates. Here, we present the first automatic cGMP-level production of [18F]P10A-1910 and translational PET/MRI study in living human brains. Successful one-step radiolabeling of [18F]P10A-1910 on a GE TRACERlab FX2N synthesis module was realized via two different methods. First, formulated [18F]P10A-1910 was derived from heating spirocyclic iodonium ylide in a tetra-n-butyl ammonium methanesulfonate solution. At the end of synthesis, it was obtained in non-decay corrected radiochemical yields (n.d.c. RCYs) of 12.4 ± 1.3%, with molar activities (MAs) of 90.3 ± 12.6 μmol (n = 7) (Method I). The boronic pinacol ester combined with copper and oxygen also delivered the radioligand with 16.8 ± 1.0% n. d.c. RCYs and 77.3 ± 20.7 GBq/μmol (n = 7) MAs after formulation (Method II). The radiochemical purity, radionuclidic purity, solvent residue, sterility, endotoxin content and other parameters were all validated for human use. Consistent with the distribution of PDE10A in the brain, escalating uptake of [18F]P10A-1910 was observed in the order of cerebellum (reference region), substantial nigra, caudate and putamen. The non-displaceable binding potential (BPND) was estimated by simplified reference-tissue model (SRTM); linear regressions demonstrated that BPND was well correlated with the most widely used semiquantitative parameter SUV. The strongest correlation was observed with SUV(50–60 min) (R2 = 0.966, p < 0.01). Collectively, these results indicated that a static scan protocol could be easily performed for PET imaging of PDE10A. Most importantly, that [18F]P10A-1910 is a promising radioligand to clinically quantify PDE10A.

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“…The experimental procedures were conducted as previous reports with minor modifications. 40,41,43,44 All chemicals were ordered from commercial suppliers and used in the synthesis without further purification. The NMR spectra were recorded on 300 MHz Bruker and/or 500 MHz Varian spectrometers at room temperature, and 1 H NMR spectra and 13 C NMR spectra were recorded at 300 MHz/75 MHz and 500 MHz/126 MHz, respectively.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Imaging of Transmembrane AMPA Receptor Regulatory Proteins by Positron Emission Tomography

Kumata

Rong

et al. 2022

J. Med. Chem.

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The transmembrane α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8) constitutes an auxiliary subunit of AMPA receptors, which mediates various brain functions including learning and memory. TARP γ-8 has emerged as a promising therapeutic target for central nervous system disorders. Despite considerable efforts, previously reported TARP γ-8 PET radioligands, such as [ 11 C]TARP-1903 and [ 11 C]TARP-1811 series, were plagued by limited brain uptake and/or high nonspecific binding in vivo. Herein, we developed two novel 11 C-labeled probes, [ 11 C]8 and [ 11 C]15 (also named as [ 11 C]TARP-2105), of which the latter exhibited a reasonable brain uptake as well as specific binding toward TARP γ-8 both in vitro and in vivo, as confirmed by blocking experiments with the commercially available TARP γ-8 inhibitor, JNJ-55511118 in the TARP γ-8-rich hippocampus. Overall, [ 11 C]15 exhibited promising tracer characteristics and proved to be a lead positron-emission tomography ligand for the non-invasive quantification of TARP γ-8 in the mammalian brain.

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Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold

Cited by 9 publications

References 56 publications

Development of High Brain-Penetrant and Reversible Monoacylglycerol Lipase PET Tracers for Neuroimaging

Development of High Brain-Penetrant and Reversible Monoacylglycerol Lipase PET Tracers for Neuroimaging

Easily automated radiosynthesis of [18F]P10A-1910 and its clinical translation to quantify phosphodiesterase 10A in human brain

Imaging of Transmembrane AMPA Receptor Regulatory Proteins by Positron Emission Tomography

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