Development and preclinical evaluation of 11C- and 18F-labelled radioligands for PET imaging of alpha7 nAChRs in the brain

本项目旨在利用正电子发射断层扫描(PET)技术确定A7烟碱型乙酰胆碱受体(A7 NAChR)非侵入性定量显像的临床前候选放射性配基，并探讨A7 nAChR PET显像作为脑内炎症过程生物标志物的可行性。A7nAChR作为神经递质乙酰胆碱的中枢和外周效应的主要调节因子，其调节的生理过程表明在治疗神经精神疾病和某些形式的癌症方面具有很高的治疗潜力。因此，在生理和病理条件下，通过PET对A7nAChR的可用性进行成像，对于评估和验证当前的诊断和药物开发概念具有很高的兴趣。在A7 nAChR的临床研究中大规模应用这种成像模式的一个主要障碍是，在脑摄取、靶点特异性和新陈代谢方面，临床适用的A7 nAChR放射性示踪剂的开发具有科学挑战性。通过分析到目前为止在用于成像A7nAChRs的PET放射性示踪剂的分子设计中所获得的知识，可以明显地看出，与重氮二环酮的核心结构相关的放射性示踪剂是最有前途的一类化合物。我们的策略是通过数据驱动的实验方法设计、评估和鉴定用于11C和18F标记的新型恶二唑基-重氮双环克罗烷A7nAChR配体。随后，将进行临床前生物学评估，以验证新化合物未来转化为更有效的PET脑内A7 nAChR成像的潜力。A7nAChR PET作为诊断工具的临床适用性将进一步通过成像研究进行评估，研究重点是这种特殊受体的可获得性中与炎症相关的变化。由于A7 nAChRs对于调节大脑中炎性小胶质细胞的活动具有相当重要的作用，我们的目标是验证我们以前开发的、目前最适合的PET放射性示踪剂[18F]NS10743用于可视化和量化阿尔茨海默氏病和中风的神经炎症过程的潜力。这一目标将通过在两个物种中应用的两种基于[18F]NS10743的成像方法的组合来实现，即使用死后脑组织的放射自显影研究和应用于莱比锡大型动物缺血性中风模型的PET研究，这最终将提高新型A7 nAChR放射示踪剂[18F]NS10743的成像潜力估计的可靠性，预计将在一般的临床PET研究中应用。综上所述，该项目有可能首次通过应用PET技术获得活脑中A7 nAChRs的非侵入性和定量获取，这对改善一些大脑疾病的诊断和药物研究具有重要意义。

This project aims at identifying preclinical candidate radioligands for quantitative non-invasive imaging of a7 nicotinic acetylcholine receptor (a7 nAChR) by positron emission tomography (PET) and to investigate the suitability of a7 nAChR PET imaging as biomarker for inflammatory processes in the brain. The physiological processes modulated by a7 nAChR as one predominant regulator of the central and peripheral effects of the neurotransmitter acetylcholine suggest high therapeutic potential in treating neuropsychiatric disorders as well as certain forms of cancer. Accordingly, imaging of a7 nAChR availability under physiological and pathological conditions by PET is of high interest for the evaluation and validation of current diagnostic and drug development concepts. A main hurdle for a larger implementation of this imaging modality in clinical research on a7 nAChR is the scientifically challenging development of clinically applicable a7 nAChR radiotracers with respect to brain uptake, target specificity, and metabolism. By analysis of the knowledge obtained so far in the molecular design of PET radiotracers for imaging a7 nAChRs it gets evident that radiotracers related to the core structure of diazabicyclononanes are the most promising class of compounds. Our strategy is to design, evaluate, and identify by a data-driven experimental approach novel oxadiazolyl-diazabicyclononane a7 nAChR ligands for 11C- and 18F-radiolabelling. Subsequently, preclinical biological evaluation will be performed to validate the potential of the new compounds for future translation into more effective imaging of a7 nAChR in brain by PET. The clinical applicability of a7 nAChR PET as diagnostic tool will furthermore be assessed by imaging studies focussing on inflammation-related changes in the availability of this particular receptor. As a7 nAChRs are of considerable importance for the regulation of the inflammatory microglia activity in brain, we aim to validate the potential of our previously developed and currently most suitable PET radiotracer [18F]NS10743 to visualise and quantify neuroinflammatory processes in Alzheimers disease and stroke. This objective will we achieve by a combination of two [18F]NS10743-based imaging approaches applied in two species, i.e. autoradiography studies using post-mortem brain tissue and PET studies applied in the Leipzig large animal model of ischemic stroke, which finally will improve the reliability of an estimation of the imaging potential of the novel a7 nAChR radiotracer [18F]NS10743 to be expected in clinical PET studies in general. Taken together, this project has the potential to for the first time gaining non-invasive and quantitative access to a7 nAChRs in the living brain by employing the PET technology, with important implications to improve diagnosis and drug research in a number of brain disorders.