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

用于大脑 α7 nAChR PET 成像的 11C 和 18F 标记放射性配体的开发和临床前评估

• 批准号: 192462798
• 负责人: Professor Dr. Henryk Barthel
• 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: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/192462798?language=en
• 关键词: Development; preclinical; evaluation; 11C; 18F

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.

本项目旨在通过正电子发射断层扫描（PET）确定用于a7烟碱乙酰胆碱受体（a7 nAChR）定量无创成像的临床前候选放射配体，并研究a7 nAChR PET成像作为脑炎症过程生物标志物的适用性。作为神经递质乙酰胆碱中枢和外周作用的主要调节因子，a7 nAChR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，PET成像a7 nAChR的可用性对当前诊断和药物开发概念的评估和验证具有很高的意义。这种成像方式在a7 nAChR临床研究中广泛应用的一个主要障碍是临床应用的a7 nAChR放射性示踪剂在脑摄取、靶特异性和代谢方面的科学挑战。通过对目前PET示踪剂分子设计知识的分析，发现与重氮杂环酮核心结构相关的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放射性标记的新型恶二唑-重氮杂环壬烷a7 nAChR配体。随后，将进行临床前生物学评估，以验证新化合物的潜力，以便将来转化为PET更有效地成像脑a7 nAChR。a7 nAChR PET作为诊断工具的临床适用性将进一步通过关注该特定受体可用性的炎症相关变化的影像学研究来评估。由于a7 nachr在脑炎性小胶质细胞活动的调控中具有相当重要的作用，我们的目标是验证我们之前开发的、目前最合适的PET放射性示踪剂[18F]NS10743在阿尔茨海默病和中风中可视化和量化神经炎症过程的潜力。我们将通过结合两种[18F]基于NS10743的成像方法来实现这一目标，即采用死后脑组织进行放射自显影研究，以及在莱比锡缺血性卒中大动物模型中进行PET研究，最终提高新型a7 nAChR放射性示踪剂[18F]NS10743在临床PET研究中的成像潜力估计的可靠性。综上所述，该项目有可能首次利用PET技术获得活体大脑中a7个nachr的非侵入性和定量访问，这对改善许多脑部疾病的诊断和药物研究具有重要意义。