Development And Research Of Novel PET Tracers For The Diagnosis Of Central Nervous System Diseases

The central nervous system(CNS)is the most critical part of the human,its dysfunction and structural damage can cause serious CNS diseases.These diseases include,generally,neurodegenerative diseases such as cerebral ischemic stroke,Alzheimer’s disease,Parkinson’s disease,and epilepsy,as well as psychiatric diseases such as anxiety,depression,and neurodevelopmental disorders and brain tumors.Positron Emission Tomography(PET),a non-invasive,highly sensitive,and specific in vivo imaging method,is the most representative modern molecular imaging technique.A wide range of PET tracers can reflect the functional and metabolic changes of organs and tissues at the cellular and molecular levels according to different application scenarios.Therefore,PET is very suitable for conducting research related to CNS diseases.With the efforts of researchers,nearly 100 CNS targets have been designed with PET tracers for research applications.However,compared with the thousands of potential targets in the CNS,it is still necessary to continue to promote the development and application of PET tracers for CNS research.Owing to the characteristics of radioactivity,short half-life,and trace level,the production of PET tracers should be carried out on automatic radiosyntheizers.In the past two decades,radiosynthesizers have continuously updated to meet the rapidly growing demand for types and production of PET tracers and to accommodate the rapidly evolving radiolabeling methods.In this thesis,I have developed and manufactured our PET tracer radiosynthesizer,and developed and applied various new PET tracers for CNS diseases using our own equipment.The first part was the development of a novel tracer[18F]safinamide based on the Parkinson’s disease drug safinamide.Since safinamide also has therapeutic effects on other neurodegenerative diseases such as ischemic stroke,Alzheimer’s disease,and epilepsy,[18F]safinamide has potential applications for diagnosing various neurodegenerative diseases.The high affinity binding to monoamine oxidase B of[18F]safinamide was verified with cellular and animal experiments,and imaging studies of[18F]safinamide in rats,a model of cerebral ischemic stroke,was carried out.However,it was found that the dataanalysis of[18F]safinamide as a multi-target binding PET tracer is complicated,and it is challenging to perform kinetic model construction.In the second part of the work,a clinical PET diagnostic study of depression/anxiety disorders was conducted using[18F]MK-9470,a high-affinity tracer of Cannabinoid Receptors Type 1(CB1R),to change the current situation of complex mechanistic studies of depression/anxiety mechanisms and lack of biological evaluation criteria for diagnosis.The results showed that CB1R expression differences between patients with depressive/anxiety disorders and normal subjects could be detected by PET.Subsequently,a novel PET tracer[18F]FEO-CPOM targeting CB1R was developed to address the deficiencies of[18F]MK-9470 brain entry efficiency and cannabinoid receptor selectivity,a series of biological evaluations were launched,and similar conclusions to those of[18F]MK-9470 clinical studies were obtained in PET imaging studies in depressed mouse model rats.In the third part,to visualize neuroinflammation,a prevalent CNS disease,the cannabinoid receptor type 2(CB2R),which has only been recognized as a valuable point for CNS applications in recent years,was chosen as a research target.A derivative of triaryl sulfonamide was selected as the lead compound to develop the novel PET tracer[18F]FEO-TaS,which was demonstrated on the cell.The high affinity and selectivity of[18F]FEO-TaS for binding to CB2R were demonstrated by cellular and ex vivo experiments.PET studies with[18F]FEO-TaS in normal and lipopolysaccharideinduced neuroinflammatory rats revealed increased uptake of[18F]FEO-TaS in the latter,but the extremely low brain uptake rate severely limits further studies of[18F]FEO-TaS.The fourth part of the thesis is that we developed a molecular imaging tracers with PET/magnetic resonance/fluorescence tri-modality imaging capabilities used in mesenchymal stem cells to address the shortcomings of a single imaging modality in the diagnosis of CNS diseases.Several biological evaluations and validation of imaging functions at the cellular level were developed to achieve a targeted diagnosis of CNS diseases with the help of mesenchymal stem cells.