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

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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.