PET Radiotracers to Evaluate Tumor Multidrug Resistance

PET 放射性示踪剂评估肿瘤多药耐药性

• 批准号: 7223360
• 负责人: MARK A GREEN
• 金额: $ 4.57万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-08 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223360
• 关键词: P glycoprotein; athymic mouse; chemical synthesis; drug design /synthesis /production; gallium; high performance liquid chromatography; intracellular transport; ligands; multidrug resistance; neoplasm /cancer diagnosis; neoplasm /cancer pharmacology; positron emission tomography; protein transport; radiopharmacology; radiotracer; stereochemistry

DESCRIPTION (provided by applicant): The objective of this project is the development of novel gallium radiopharmaceuticals for non-invasive assessment of tumor multidrug resistance using positron emission tomography (PET). The project expands upon preliminary studies showing that radiogallium complexes of hexadentate Schiff-base ligands can serve as substrates for transport by the MDR1 P-glycoprotein (MDR1 Pgp) involved in tumor multidrug resistance. Such gallium radiopharmaceuticals are expected to be useful in PET studies to quantify tumor MDRI Pgp transport function in vivo. Accordingly, the Specific Aims for this project are: 1. Radiopharmaceutical Design and Synthesis; 2. Radiopharmaceutical Evaluation as MDR1 Pgp Transport Substrates In Vitro; and 3. Radiopharmaceutical Evaluation as MDRI Pgp Transport Substrates In Vivo. Novel linear hexadentate ligands, designed to afford an N4022- metal coordination sphere, will be synthesized for examination of structure-activity relationships defining optimal performance as MDR1 Pgp transport substrates. Tracer screening itz vitro will employ cultured tumor cells for assessment of agent selectivity for drug-sensitive vs. drug resistant cells, MDR1 Pgp transport kinetics, and relative MDR1 Pgp binding affinity. Athymic mice with drug-sensitive and drug-resistant tumor xenografts will be employed for assessing MDRI Pgp modulation of radiopharmaceutical localization in tumors in vivo.

描述（由申请人提供）： 该项目的目的是使用正电子发射断层扫描（PET）的非侵入性评估肿瘤多药耐药性的新型甘露仪式放射性药物的开发。该项目扩展了初步研究，表明六化酸盐基体配体的放射性体积可以用作由MDR1 P-糖蛋白（MDR1 PGP）运输的底物。预计此类放射性药物在PET研究中有用，以定量体内肿瘤MDRI PGP转运功能。因此，该项目的具体目的是：1。放射性药物设计和合成； 2。在体外作为MDR1 PGP转运底物的放射性药物评估；和3。作为MDRI PGP转运底物在体内的放射性药物评估。旨在提供N4022-金属配位球体的新型线性六亚源配体将合成，以检查将最佳性能定义为MDR1 PGP传输底物的结构活性关系。示踪剂筛选ITZ Veltro将利用培养的肿瘤细胞评估药物敏感性与耐药细胞，MDR1 PGP转运动力学和相对MDR1 PGP结合亲和力的药物选择性。将使用具有药物敏感和耐药性肿瘤异种移植的无胸腺小鼠来评估体内肿瘤中放射性药物定位的MDRI PGP调节。