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

本研究项目的目标是开发用于正电子发射断层扫描（PET）研究的放射性标记丁基胆碱酯酶（BChE）生物标志物。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片段不可逆地转移到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出来，对人BChE具有纳米级亲和力，对乙酰胆碱酯酶（hAChE）具有良好的选择性。这些先导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，以开发最适合的化合物作为PET放射性示踪剂，具有最佳的代谢和物理化学特性。此外，将开发和建立用于制备11C和18F类似物的合适合成途径，重点是18F标记的放射药物。放射性标记的高活性和选择性不可逆BChE抑制剂将被评价为应用小动物PET对小鼠脑BChE进行PET研究的放射性示踪剂。由于其创新的作用模式，这些化合物代表了可视化和量化脑BChE作为神经退行性疾病诊断的重要靶点的新方法。

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.