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核心技术专利：CN118964589B侵权必究
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鉴定和临床前开发一种 2,5,6-三取代的氟化吡啶衍生物作为正电子发射断层扫描成像大麻素 2 型受体的放射性配体。

Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors.

机构信息

Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, 4070 Basel, Switzerland.

出版信息

J Med Chem. 2020 Sep 24;63(18):10287-10306. doi: 10.1021/acs.jmedchem.0c00778. Epub 2020 Sep 1.

DOI:10.1021/acs.jmedchem.0c00778
PMID:32787079
Abstract

Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity ( for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18- exhibited outstanding performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% ( = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [F]RoSMA-18- showed exceptional CB2 attributes as demonstrated by autoradiography, biodistribution, and positron emission tomography (PET). Further, [F]RoSMA-18- was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [F]RoSMA-18- is a promising CB2 PET radioligand for clinical translation.

摘要

尽管大麻素类型 2 受体 (CB2) 在神经炎症过程中具有广泛的意义，但目前在临床常规中缺乏合适的 CB2 靶向探针。在这项工作中，我们合成了 15 个氟代吡啶衍生物，并测试了它们对 CB2 和 CB1 的结合亲和力。RoSMA-18 对 CB2 的亲和力(sub-nanomolar affinity)为 0.8 nM，对 CB1 的选择性因子(selectivity factor)超过 12,000，表现出出色的性能特征，并以平均放射性化学产率 10.6 ± 3.8%（n = 16）和摩尔活度为 52 至 65 GBq/μmol（放射化学纯度 > 99%）进行放射性标记。[F]RoSMA-18 的放射性自显影、生物分布和正电子发射断层扫描（PET）显示了其出色的 CB2 属性。此外，[F]RoSMA-18 还用于检测人死后 ALS 脊髓组织中 CB2 的上调。总的来说，这些结果表明[F]RoSMA-18 是一种有前途的用于临床转化的 CB2 PET 放射性配体。

相似文献

[1]
Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors.

J Med Chem. 2020-9-24

[2]
Evaluation of [F]RoSMA-18-d as a CB2 PET Radioligand in Nonhuman Primates.

ACS Chem Neurosci. 2023-10-18

[3]
Structure-Activity Relationship Studies of Pyridine-Based Ligands and Identification of a Fluorinated Derivative for Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors.

J Med Chem. 2019-12-5

[4]
Discovery of a fluorinated 4-oxo-quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2.

J Neurochem. 2016-9

[5]
Evaluation of 4-oxo-quinoline-based CB2 PET radioligands in R6/2 chorea huntington mouse model and human ALS spinal cord tissue.

Eur J Med Chem. 2018-1-5

[6]
Synthesis and Preclinical Evaluation of Fluorinated 5-Azaindoles as CB2 PET Radioligands.

ACS Chem Neurosci. 2023-8-16

[7]
Synthesis, radiolabeling and evaluation of novel 4-oxo-quinoline derivatives as PET tracers for imaging cannabinoid type 2 receptor.

Eur J Med Chem. 2015-1-13

[8]
Design, synthesis and preliminary evaluation of (18)F-labelled 1,8-naphthyridin- and quinolin-2-one-3-carboxamide derivatives for PET imaging of CB2 cannabinoid receptor.

Bioorg Med Chem Lett. 2015-6-15

[9]
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J Med Chem. 2016-9-8

[10]
Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor.

J Neurochem. 2013-7-19

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[2]
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EJNMMI Radiopharm Chem. 2024-12-23

[3]
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Chem Sci. 2024-10-3

[4]
Translational Preclinical PET Imaging and Metabolic Evaluation of a New Cannabinoid 2 Receptor (CBR) Radioligand, ()--(3-(2-(2-[F]Fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide.

ACS Pharmacol Transl Sci. 2024-9-13

[5]
A Highly Potent, Orally Bioavailable Pyrazole-Derived Cannabinoid CB2 Receptor- Selective Full Agonist for Studies.

ACS Pharmacol Transl Sci. 2024-7-9

[6]
Highly Selective Drug-Derived Fluorescent Probes for the Cannabinoid Receptor Type 1 (CBR).

J Med Chem. 2024-7-25

[7]
A highly potent, orally bioavailable pyrazole-derived cannabinoid CB2 receptor-selective full agonist for studies.

bioRxiv. 2024-4-29

[8]
Synthesis, Structure-Activity Relationships, Radiofluorination, and Biological Evaluation of [F]RM365, a Novel Radioligand for Imaging the Human Cannabinoid Receptor Type 2 (CB2R) in the Brain with PET.

J Med Chem. 2023-10-26

[9]
Rational Design, Synthesis, and Evaluation of Fluorescent CB Receptor Ligands for Live-Cell Imaging: A Comprehensive Review.

Pharmaceuticals (Basel). 2023-8-31

[10]
Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years.

Pharmacol Rev. 2023-9

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