Radiosynthesis Of ¹⁸F-Labeled Natural Active Drugs And Their In Vivo Property Evaluation And PET/CT Imaging

Natural active compounds and their structural analogues play ver y important roles in the process of drug discovery and development,such as active components of Chinese herbal medicine and essential amino acids of human body.However,Positron nuclide labeling such as ^{1 8}F and PET/CT imaging have not been widely used within the realm of Traditional Chinese Medicine and natural herbal materia medica.Erianin,an extract of Dendrobium,is a potential antitumor drug with unique molecular structure and significant antitumor effect.There are many studies on the in vivo and in vitro antitumor effects of Erianin and its derivatives,but their in vivo behavior,distribution and pharmacokinetics have not been paid attention to.As a natural amino acid,tryptophan regulates tumor immune response through metabolic pathway,which has attracted much attention.Meanwhile,radionuclide ^{1 1}C and ^{1 8}F labeled tryptophan PET/CT imaging shows good image contrast and application potential of brain tumor model with,but they have not been studied in liver cancer imaging and tumor immunotherapy evaluation.Therefore,the purpose of this thesis intended to carry out the radiochemical synthesis,in vivo and in vitro properties evaluation,and liver tumor Micro PET/CT imaging of ^{1 8}F-labeled erianin derivative ^{1 8}F-FEE and tryptophan derivative ^{1 8}F-FETrp.This thesis consists of the following four chapters:In the first chapter,the application of natural materia medica in tumor treatment was briefly introduced,and the evaluation and analysis of the in vivo distribution behavior of natural products by using radionuclide labeling and PET/CT imaging was summarized,and then the main research contents of this thesis was introduced.In the second chapter,^{1 8}F-radiolabeling preparation and Micro PET/CT imaging of ^{1 8}F-FEE was invetigated,which is a derivative of erianin,an active ingredient of Anticancer Traditional Chinese medicine.Firstly,series factors affecting ^{1 8}F-labeling efficient of ^{1 8}F-FEE were optimized,and a stable and reliable strategy for the radiochemical synthesis and analysis of^{1 8}F-FEE was established.Secondly,the in vitro properties of ^{1 8}F-FEE,including stability,partition coefficient,plasma protein binding rate and cell uptake rate,were systematically assessed.Then,the in vivo distribution behavior and pharmaceutical properties of ^{1 8}F-FEE were evaluated b y biodistribution and small animal Micro PET/CT.The related results showed that ^{1 8}F-FEE had good stability in vitro,high plasma protein binding rate,rapid distribution in vivo and then“fast followed by slow”clearance.Importantly,the tumor lesion distribution of ^{1 8}F-FEE in Hep G2 liver cancer model is apparent,indicating that erianin derivatives can enter the tumor area in large quantities and retain for a long time.Therefore,the above experimental results offer an intuitive experimental evaluation means for the in vivo distribution behavior and pharmaceutical properties of erianin derivatives.In the third chapter,radiosynthesis and liver cancer Micro PET/CT imaging of ^{1 8}F-labeled tryptophan derivative ^{1 8}F-FETrp because tryptophan is a human essential amino acid with antitumor immunomodulatory properties.Firstly,the radiochemical synthesis and analysis method of ^{1 8}F-FETrp was successfully establis hed.Secondly,the in vitro properties of ^{1 8}F-FETrp were evaluated by partition coefficient,plasma protein binding rate and cell uptake rate.Then,the in vivo properties and distribution of ^{1 8}F-FETrp were surveyed by biodistribution and small animal Micro PET/CT imaging.The experimental results showed that ^{1 8}F-FETrp had appropriate plasma protein binding rate and high cell uptake rate.^{1 8}F-FETrp PET/CT imaging of SMMC7721 liver cancer model showed excellent imaging contrast,which could significantly distinguish the tumor from the surrounding tissues.Therefore,^{1 8}F-FETrp has good PET/CT imaging ability of liver cancer and strong clinical trans lation potential.In the fourth chapter,it is the summary of this thesis and perspective.It briefly summarizes the main experimental results in the thesis.It is worth paying attention to the extensive distribution and long-time residence in Hep G2 tumor of ^{1 8}F-FEE,and the excellent PET/CT imaging effect in SMMC7721 liver cancer of ^{1 8}F-FETrp.Finally,this thesis looks forward to the application of ^{1 8}F-radiolabeling and PET/CT imaging into the distribution and pharmaceutical properties of active components of traditional Chinese medicine,as well as the trans lation of ^{1 8}F-FETrp and^{1 8}F-labeled amino acids as new tumor PET/CT molecular imaging probes.