In vivo imaging of tropomyosin receptor kinase (Trk) status in cancer for therapeutic outcome prediction with Positron Emission Tomography (PET) and investigation of Trk status linked to neurodegenerative disease progression

人脑是中枢神经系统(CNS)的器官。除了头骨，大脑还受到血脑屏障的保护，血脑屏障将大脑与血液隔离。尽管如此，人类的大脑很容易受到损伤和疾病的影响。功能障碍或紊乱可能会导致癌症或神经退行性疾病，如痴呆症。已知原肌球蛋白受体激酶(Trks)在多种神经源性和非神经源性人类癌症中驱动肿瘤的发生和转移。此外，Trk表达和信号的失调被认为是许多神经退行性疾病的特征，包括帕金森氏症、亨廷顿氏症和阿尔茨海默病。神经母细胞瘤是幼儿最常见的癌症。目前，神经母细胞瘤的诊断是基于组织活检。在这种状态下，癌症通常已经扩散。治疗方法可能包括手术、放射、化疗和干细胞移植。该项目将通过研究非侵入性方法来防止这些令人不快的手术，非侵入性方法将在癌症扩散之前进行。将利用正电子发射断层扫描(PET)的体内成像技术来研究和设计用于神经母细胞瘤成像和Trk分期的氟-18-化合物。PET是一种高灵敏度、完全可量化的非侵入性成像技术，基于针对大脑中特定受体的放射性示踪剂。此外，使用氟-18类似物的Trk成像将扩展到神经退行性疾病，如阿尔茨海默病、S病(AD)。AD是老年人中最常见的痴呆症，是记忆和认知功能丧失的总称。最初的症状因人而异，例如找词或推理障碍可能预示着AD的早期阶段。尽管目前的阿尔茨海默氏症治疗方法无法阻止阿尔茨海默氏症的发展，但它们可以暂时减缓痴呆症症状的恶化。检测大脑的早期变化对于提高阿尔茨海默病患者的生活质量是必要的。目前还没有方法学来评估神经母细胞瘤和活体人脑中Trks的空间和/或时间变化。我们的目标是在Schirrmacher‘S团队先前设计的化合物的基础上，开发一种用于正电子发射断层扫描的非侵入性氟-18标记显像剂，以评估TrkB疾病与神经母细胞瘤和AD的相关性。神经母细胞瘤和AD研究界需要一种非侵入性的定量显像剂来推动Trk相关癌症和脑研究超越临床前阶段。

The human brain is an organ of the central nervous system (CNS). Apart from the skull, the brain is protected by the blood-brain-barrier, which isolates it from the bloodstream. In spite of that, the human brain is susceptible to damage and disease. Dysfunctions or disorders could lead to cancer or neurodegenerative diseases, such as dementia. Tropomyosin receptor kinases (Trks) are known to drive tumorigenesis and metastatic potential in a wide range of neurogenic and non-neurogenic human cancers. Also a dysregulation of Trk expression and signaling is recognized as a hallmark of numerous neurodegenerative diseases including Parkinson's, Huntington's and Alzheimer's disease.Neuroblastoma is the most common cancer in young children. At the present day, the diagnosis of neuroblastoma is based on tissue biopsy. At this state the cancer has usually already spread. Treatments may include surgery, radiation, chemotherapy and stem cell transplantation. This project will prevent these unpleasant procedures by studying non-invasive methods, which will take place before the cancer spreads. The synthesis and design of fluorine-18-compounds for neuroblastoma imaging and Trk staging by using in vivo imaging with positron emission tomography (PET) will be investigated and evaluated. PET is a highly sensitive, fully quantifiable non-invasive imaging technology based on radioactive tracers targeting specific receptors in the brain.Furthermore, Trk imaging with the fluorine-18-analogue will be extended towards neurodegenerative diseases such as Alzheimer´s disease (AD). AD is the most common form of dementia among older adults, a general term for loss of memories and cognitive functioning. The first symptoms vary from person to person, such as word-finding or impaired reasoning may signal the very early stages of AD. Although current Alzheimer's treatments cannot stop Alzheimer's from progressing, they can temporarily slow the worsening of dementia symptoms. Detection of early changes in the brains are necessary to improve quality of life for those afflicted with AD. There is currently no methodology to evaluate in vivo spatial and/or temporal changes of Trks in neuroblastoma and the live human brain. We aim to develop a non-invasive fluorine-18-labeled imaging agent for Positron Emission Tomography (PET) based on previously designed compound of the Schirrmacher´s group to evaluate TrkB disease associations in neuroblastoma and AD. The neuroblastoma- as well as AD research community is in need of a noninvasive quantitative imaging agent to advance Trk related cancer- and brain research beyond the pre-clinical stage.