Preliminary Studies On New Positron Emission Tomography Radiopharmaceuticals For Alzhemer`s Disease And Apoptosis

The main work of this dissertation comprises two parts: (1) The research of ¹⁸F radiolabeled resveratrol derivatives as new APs imaging agents; (2) The study on new radiolabeled chelating agent of Zinc ion with dipicolylamine as apoptosis imaging agents in tumor mice.Part One: a series of resveratrol derivatives as new APs imaging agents were synthesized according to the special affinity of resveratrol with Aβand characteristics of the chemical structure of BAY94-9172. BAY94-9172 and its two precursors were synthesized through a short route in this paper, and the mesylate derivative without protection of methylamino by (Boc)2O should be a new precursor of BAY94-9172, which was confirmed through the radiosynthesis of [¹⁸F]BAY94-9172 with the two precursors. In addition, [¹⁸F]BAY94-9172 was automated synthesized by one step fluorination of the new precursor in this work. The radiolabeled compounds were obtained after Sep Pak C18 purification within shorter radiosynthesis time and the radiochemical purity was over 95%. The influence in PET imaging for the chemical purity of radiolabeled compounds would be studied in future work.The biodistribution of ¹⁸F-labeled resveratrol derivatives showed that the labeled compounds were rapidly distributed widely to all organs in normal rice after intravenous injection within 2 min, and were metabolized from liver and spleen. Comparation to [¹⁸F]BAY94-9172, [¹⁸F]12 showed a low initial brain uptake, but followed by a rapid washout with a ratio of 2 min to 60 min brain uptake of 9.2. [¹⁸F]26 and [¹⁸F]45 exhibited excellent initial brain penetrations and moderate brain washout in normal mice (the ratios of 2 min to 60 min brain uptake were 2.6 and 3, respectively.). So [¹⁸F]26 and [¹⁸F]45 have some potentials as tracer for PET imaging Aβplaques in Alzheimer`s disease. PET images showed that the uptakes were seen in normal or AD module mice for the labeled compounds, but the detailed information about uptake and distribution of labeled compounds in mice brain could not be obtained for the poor resolution of clinical PET, and the comprehensive evaluation of these compounds should be combined with affinity with Aβin vitro in the further work. Part Two: The increase of zinc ion concentration in cell and the appearance of phosphatidylserine (PS) on the cell surface were two hallmarks of cells in apoptosis. A chelating agent of zinc ion with dipicolylamine was successfully synthesized in this work, and three ¹⁸F-labeled compounds (with and without zinc ion) were obtained from being attached with two different ¹⁸F-labeled groups, which were potential apoptosis imaging agents with the zinc ion and PS as targets. [¹⁸F]58 and its chelate with zinc ion were rapidly distributed widely in normal mice after intravenous injection, and were metabolized mainly through liver and kidneys. PET images in tumor mice showed that uptake in tumors were discernible to that in other organs for the three ¹⁸F-labeled dipicolylamine derivatives. The images with heterogeneous intensity were seen in tumors treated with adriacin for [¹⁸F]58 and its chelate with zinc ion, which proved that the compounds [¹⁸F]58 and its chelate with zinc ion exhitited selective for some apoptic and necrotic cells. The studies of clinical pathology of tumors and mechanisms of affinity to apoptotic cells in vitro are ongoing in future.