A Study On Design, Synthesis And Activity Test Of Novel Tumor Hypoxia Imaging Agents

Many studies have indicated that hypoxia is a common phenomenon in animal and human solid tumors. It has become apparent that hypoxia not only participates in resistance to radiotherapy and many chemo-therapeutic agents, but also can profoundly affect the malignation process. However, it is not possible to predict tumor hypoxia in individual patient as there is both inter- and intra- tumoral variation in oxygen status and no consistent relationship between hypoxic fraction and tumor size or phase.Nuclear medicine technology offers a non-invasive and widely available clinical method for demonstrating tumor hypoxia. The study of hypoxia imaging agents, which is derived from the application of radiosensitizer in hypoxic tissues, has been a hotspot in the field of radiopharmaceuticals. Hypoxia imaging can detect the position and number of the hypoxic tissues. According to the information, doctors can adopt optimal treatment, therefore improve the efficiency of radio- and chemo- therapy.Early interest centered around labeled nitroimidazole compounds, and did find several agents, such as ¹⁸F-MISO, ¹²³I-IAZA and ⁹⁹Tc^m-BMS181321. It is perhaps surprising, given the concentration on and interest in nitroimidazole analogues, which in vitro and animal studies have demonstrated that the ⁹⁹Tc^m complexes of the core ligands of above-mentioned compounds showed even greater hypoxia selectivity. A prototype formulation of one of these compounds is Bn(AO)₂ (4,9-diaza-3,3,10,10-tetramethyldodecan-2,ll-dione dixime), which is also known as HL91. Preclinical and clinical studies have indicated that ⁹⁹Tc^m-Bn(AO)₂ is a promising compound to be used as hypoxia imaging agent in oncology and other medical applications.The aim of the present study was to seek for novel hypoxia imaging agents with simple structure and good performance, and if possible, elucidate the mechanism of the retention of hypoxia agents in hypoxic tissues to a certain degree. Our research included four parts: design and synthesis of amine oximes and other compounds as ligands, label them...