PET Radiotracers to Evaluate Tumor Multidrug Resistance

描述（由申请人提供）： 本项目的目标是开发新型镓放射性药物，用于使用正电子发射断层扫描（PET）非侵入性评估肿瘤多药耐药性。该项目扩展了初步研究，表明放射性镓配合物的六齿席夫碱配体可以作为底物的MDR 1 P-糖蛋白（MDR 1 Pgp）参与肿瘤多药耐药的运输。预期此类镓放射性药物可用于PET研究以量化体内肿瘤MDRI Pgp转运功能。因此，该项目的具体目标是：1。放射性药物设计与合成; 2.放射性药物作为MDR 1 Pgp转运底物的体外评价; 3.放射性药物作为MDRI Pgp转运底物的体内评价。新的线性六齿配体，旨在提供N4022-金属配位球，将被合成用于检查定义最佳性能作为MDR 1 Pgp转运底物的结构-活性关系。体外示踪剂筛选将使用培养的肿瘤细胞评估药物对药物敏感细胞与耐药细胞的选择性、MDR 1 Pgp转运动力学和相对MDR 1 Pgp结合亲和力。将采用具有药物敏感性和耐药性肿瘤异种移植物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。

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.