The Automated Synthesis And Biological Evaluation Of [¹⁸F]Fluoromisonidazole And The Synthesis Of 6-[¹⁸F]-L-DOPA

Aim: Positron emission tomography (PET) is an imaging modality for accurately determining regional function and biochemistry within various organs of the human body. PET has been used in oncology and other diseases. Hypoxia is the one of main characteristics of many serious diseases and widely occurs in malignant tumors, cerebral ischemia and myocardial infarction. [¹⁸F]fluoromisonidazole (¹⁸F-FMISO) is one of the most promising radiopharmaceuticals for detecting hypoxia, but its precursor is expensive and the labeling technology of ¹⁸F-FMISO needs to be improved. We improved the yield of NITTP and modified the 2-Vessel ¹⁸F-FDG module (manufactured by CTI) for producing ¹⁸F-FMISO. The biodistribution of ¹⁸F-FMISO in both normal and tumor-bearing mice as well as the use of F-FMISO PET imaging for detecting tumor hypoxia were described.Radiolabelled amino acid is another metabolic imaging agent. 6-[¹⁸F]-L-DOPA is an amino acid analogue (3,4-dihydroxy-L-phenylalanine, L-DOPA). 6-[¹⁸F]-L-DOPA plays an important role in diagnosing Pakinson's disease and some tumors. Our study discusses thepreparation of 6-[¹⁸F]-L-DOPA by asymmetric synthesis and symmetric synthesis.Methods: 1 -(2'-nitro-l'-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol (NITTP) was synthesized using glycerol as the starting material, through esterification, protection of hydroxy group and nucleophilic substitution. Various factors (such as reaction time, temperature, transfer time, evaporation time and so on) influencing the yield of the 2-vessel ¹⁸F-FDG synthesis module were studied. ¹⁸F-FMISO was synthesized automatically by nucleophilic substitution, followed by hydrolysis. The dependence of the radiochemical yield of ¹⁸F-FMISO on different reaction parameters (method of purification, reaction temperature and amount of precursor) was also investigated. ¹⁸F-FMISO solution was injected intravenously into normal and tumor-bearing mice for determining the biodistribution. Finally the PET imaging of ¹⁸F-FMISO was performed.Using 4-fluoroveratrol as starting material, the cold synthesis of 6-[¹⁸F]-L-DOPA was explored by alkylation reaction of asymmetric synthesis or condensation and hydrolysis of symmetric synthesis.Results: The ¹⁸F-FMISO precursor was synthesized with a total yield of 29%. The chemical structure was confirmed by means of ¹H-NMR and MS. The overall radiochemical yield of ¹⁸F-FMISO after decay correction was greater than 60%. The whole synthesis time was about 40 min and the radiochemical purity was greater than 98%. ¹⁸F-FMISO was found to accumulate in the S180 sarcoma.6-fluoro-L-DOPA was detected in the reaction mixtures. However, we failed to obtain the pure product because the latter was rapidly oxygenated.Conclusion: The ¹⁸F-FMISO precursor was synthesized with relatively high yield. We developed a fully automated method for the synthesis of ¹⁸F-FMISO.Though 6-Fluoro-L-DOPA has not been obtained, our present experience of its synthesis may lay the foundation for future work.