Ag(111) Carbeneporphyrinoids as Radiopharmaceuticals

Ag(111) 卡宾卟啉类放射性药物

• 批准号: 6505285
• 负责人: WILEY J YOUNGS
• 金额: $ 14.7万
• 依托单位: UNIVERSITY OF AKRON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6505285
• 关键词: biotin; breast neoplasms; carbene; drug design /synthesis /production; imidazole; immunoconjugates; laboratory rat; metal complex; metalloporphyrins; neoplasm /cancer radioimmunotherapy; nitrogenous heterocyclic compound; nonhuman therapy evaluation; pharmacokinetics; pyrroles; radionuclides; radiopharmacology; silver

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.

描述（由申请人提供）：本申请的广泛、长期目标是合成和开发一系列新的基于大环n杂环碳烯金属配合物的放射免疫偶联物，作为癌症放射治疗的治疗性放射药物。本提案的第一个目标是合成一系列新的大环，称为碳卟啉，其中一个或多个吡咯单元在卟啉环或扩展的卟啉环被n -杂环羰基取代。杨斯的研究小组已经合成了几个例子。本提案的第二个目标是合成碳卟啉类化合物的金属配合物。碳卟啉类化合物及其扩展类似物将具有新的螯合性质和空腔大小，并能与多种金属结合。作为治疗放射性药物的金属配合物的稳定性是极其重要的。n -杂环碳烯与过渡族金属和主族金属的结合非常强，目前的数据表明，与放射性药物中使用的其他大环相比，碳卟啉类化合物与金属中心的结合更强。该项目长期关注的金属将是那些在放射治疗中具有或潜在重要性的金属，如释放放射性核素的β粒子。在这方面首先勘探的金属将是111银。本研究的第三个目的是研究这些新复合物的体内外稳定性。银类碳卟啉非常稳定。本建议的第四个目标是通过连接基团，将体内稳定的金属碳卟啉类化合物与选择性靶向肿瘤细胞的靶向分子结合，产生载体，螯合剂，金属物种，称为免疫偶联物。将使用两种类型的靶向基团，硝基咪唑和生物素。本提案的第五个目标将是评估金属-碳-苯卟啉复合物及其放射免疫偶联物对细胞的影响和靶向能力。本提案的第六个目标将是确定靶向类金属碳卟啉在减少小动物癌症方面的毒性、清除率和有效性。

项目成果

Synthesis, characterization, in vitro SAR study, and preliminary in vivo toxicity evaluation of naphthylmethyl substituted bis-imidazolium salts.

• DOI: 10.1016/j.bmc.2020.115893
• 发表时间: 2021-01-15
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Southerland MR;DeBord MA;Johnson NA;Crabtree SR;Alexander NE;Stromyer ML;Wagers PO;Panzner MJ;Wesdemiotis C;Shriver LP;Tessier CA;Youngs WJ
• 通讯作者: Youngs WJ