Ag(111) Carbeneporphyrinoids as Radiopharmaceuticals

描述(申请人提供)：这项建议的广泛、长期目标是合成和开发一系列新的基于大环N-杂环卡宾金属络合物的放射免疫结合物，作为癌症放射治疗的治疗性放射性药物。这一提议的第一个目标是合成一系列新的大环，称为卡宾卟啉，其中一个或多个大环中的一个或多个吡咯单元已被N-杂环卡宾取代。杨斯的研究小组已经综合了几个例子。这项建议的第二个目标是合成卡宾卟啉类金属配合物。卡宾卟啉类化合物及其扩展的类似物将具有新颖的螯合性能和空腔大小，并将与各种金属结合。金属络合物作为治疗性放射性药物的稳定性是极其重要的。N-杂环卡宾与过渡金属和主族金属结合非常强烈，目前的数据表明，卡宾卟啉类化合物与金属中心的结合比用于放射性药物的其他大环更强。该项目长期关注的金属将是那些在放射治疗中具有或可能具有重要作用的金属，作为发射放射性核素的贝塔粒子。在这方面要探索的第一种金属将是111银。这项建议的第三个目标是研究这些新配合物的体外和体内稳定性。银卡宾卟啉类化合物非常稳定。这项提议的第四个目标是通过连接基将体内稳定的金属卡宾卟啉结合到靶向分子上，这些分子选择性地靶向肿瘤细胞，产生一种载体，螯合剂，一种将被称为免疫结合物的金属物种。将使用两种类型的靶向基团，硝基咪唑和生物素。这项提案的第五个目标将是评估金属卡宾卟啉络合物及其放射免疫结合物对细胞的影响和靶向能力。这项提案的第六个目标将是确定靶向金属卡宾卟啉类化合物在减少小动物癌症方面的毒性、清除性和有效性。

DESCRIPTION (provided by applicant): The broad, long-term objective of this proposal is the synthesis and development of a new series of radloimmunoconjugates as therapeutic radiopharmaceuticals for cancer radiation therapy based on metal complexes of macrocyclic N-heterocyclic carbenes. The first objective of this proposal is the synthesis of a new series of macrocycles, termed carbeneporphyrinods, in which one or more pyrrole units in a porphyrinoid ring or expanded porphyrinoid ring have been replaced with N-heterocyclic carbenes. Several examples have already been synthesized in the Youngs' research group. The second objective of this proposal is the synthesis of metal complexes of the carbeneporphyrinoids. The carbeneporphyrinoids and their expanded analogs will have novel chelating properties and cavity sizes and would bind to a variety of metals. The stability of the metal complexes used as therapeutic radiopharmaceuticals is extremely important. N-heterocyclic carbenes bind very strongly to transition and main group metals and current data indicate that carbeneporphyrinoids will bind more strongly to metal centers than do other macrocycles used in radiopharmaceuticals. The metals to be focused on in this project in the long term will be those that have or potentially have importance in radiation therapy as Beta particle emitting radionuclides. The first metal to be explored in this regard will be 111 Ag. The third objective of this proposal is to study the in vitro and in vivo stability of these new complexes. The silver carbeneporphyrinoids are extremely stable. The fourth objective of this proposal is to bind, by a linker group, the in vivo stable metallocarbeneporphyrinoids to targeting molecules that selectively target cancerous tumor cells producing a vehicle, chelator, metal species that will be called an immunoconjugate. Two types of targeting groups, nitroimidazoles and biotin, will be used. The fifth objective of this proposal will be to assess the impact and targeting ability of the metallocarbeneporphyrinoid complexes and their radioimmunoconjugates on cells. The sixth objective of this proposal will be to determine toxicity, clearance, and the effectiveness of the targeted metallocarbeneporphyrinoid in reducing carcinoma in small animals.