Development of radiolabelled butyrylcholinestase inhibitors as neurologigal biomarkers for molecular imaging by positron emission tomography

开发放射性标记的丁酰胆碱淤积抑制剂作为正电子发射断层扫描分子成像的神经生物标志物

• 批准号: 214496460
• 负责人: Professor Dr. Michael Decker
• 金额: --
• 依托单位: Klinik und Poliklinik für Nuklearmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/214496460?language=en
• 关键词: Development; radiolabelled; butyrylcholinestase; inhibitors; neurologigal

The goal of this research project lies in the development of radiolabeled butyrylcholinesterase (BChE) biomarkers for positron emission tomography (PET) investigations. For this purpose a novel labelling concept will be applied for the first time, in which a radiolabeled chemical moiety is irreversibly transferred to the catalytic active center of BChE (irreversible trapping). Such carbamate-based BChE inhibitors have been developed in our group with nanomolar affinity at human BChE and excellent selectivity over the isoenzyme acetylcholinesterase (hAChE). These lead structures will be further optimized by synthetic means and in vitro evaluation supported by molecular modeling studies, in order to develop the most suitable compounds as PET radiotracers with optimal metabolic and physicochemical characteristics. Additionally, suitable synthetic pathways for preparation of 11C and 18F analogs will be developed and established with a focus on 18F labelled radiophramaceuticals. The radiolabeled highly active and selective irreversible BChE inhibitors will be evaluated as radiotracers for PET-investigations of cerebral BChE in mice applying small animal PET. Due to their innovative mode of action such compounds represent a new approach to visualize and quantify cerebral BChE as important target for diagnosis of neurodegenerative disorders.

该研究项目的目标在于开发放射性标记的丁酰胆碱酯酶（BChE）生物标志物用于正电子发射断层扫描（PET）研究。为此，将首次应用一种新的标记概念，其中放射性标记的化学部分被不可逆地转移到BChE的催化活性中心（不可逆捕获）。这种基于氨基甲酸酯的BChE抑制剂已经在我们的小组中开发，对人BChE具有纳摩尔亲和力，并且对同工酶乙酰胆碱酯酶（hAChE）具有优异的选择性。这些先导化合物的结构将通过合成手段和分子模拟研究支持的体外评价进一步优化，以开发最适合作为PET放射性示踪剂的化合物，具有最佳的代谢和理化特性。此外，将开发和建立用于制备11C和18F类似物的合适的合成途径，重点是18F标记的放射性药物。放射性标记的高活性和选择性不可逆BChE抑制剂将作为放射性示踪剂进行评价，用于在应用小动物PET的小鼠中进行脑BChE的PET研究。由于其创新的作用模式，这些化合物代表了一种新的方法来可视化和定量脑BChE作为诊断神经退行性疾病的重要目标。

项目成果

Dual-Acting Cholinesterase-Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo.

• DOI: 10.1021/acs.jmedchem.9b00623
• 发表时间: 2019-10-24
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Scheiner M;Dolles D;Gunesch S;Hoffmann M;Nabissi M;Marinelli O;Naldi M;Bartolini M;Petralla S;Poeta E;Monti B;Falkeis C;Vieth M;Hübner H;Gmeiner P;Maitra R;Maurice T;Decker M
• 通讯作者: Decker M

A Novel Way To Radiolabel Human Butyrylcholinesterase for Positron Emission Tomography through Irreversible Transfer of the Radiolabeled Moiety

通过放射性标记部分的不可逆转移来放射性标记人丁酰胆碱酯酶用于正电子发射断层扫描的新方法

• DOI: 10.1002/cmdc.201600223
• 发表时间: 2016
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: E. Sawatzky;E. Al-Momani;R. Kobayashi;S. Samnick;T. Higuchi;M. Decker
• 通讯作者: M. Decker

A simple heterocyclic fusion reaction and its application for expeditious syntheses of rutaecarpine and its analogs

• DOI: 10.1016/j.tetlet.2014.04.120
• 发表时间: 2014-06-25
• 期刊: TETRAHEDRON LETTERS
• 影响因子: 1.8
• 作者: Huang, Guozheng;Roos, Dominika;Decker, Michael
• 通讯作者: Decker, Michael