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

本研究项目的目标在于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)生物标记物。为此，将首次应用一种新的标记概念，即将放射性标记的化学部分不可逆地转移到BCHE的催化活性中心(不可逆捕获法)。这种基于氨基甲酸酯的BChE抑制剂已经在我们的团队中被开发出来，在人的BChE上具有纳摩尔亲和力，并且比同工酶乙酰胆碱酯酶(HAChE)具有很好的选择性。在分子模拟研究的支持下，将通过合成手段和体外评价进一步优化这些化合物的结构，以开发出最适合作为具有最佳代谢和物理化学特性的PET放射性示踪剂的化合物。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的不可逆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，这些化合物代表了一种新的方法来可视化和量化大脑BChE，作为诊断神经退行性疾病的重要靶点。

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.