PET Radiotracers to Evaluate Tumor Multidrug Resistance

描述(由申请人提供)： 该项目的目标是开发新型的镓放射性药物，用于利用正电子发射断层扫描(PET)非侵入性评估肿瘤的多药耐药性。该项目的扩展是在初步研究的基础上进行的，该研究表明，六齿希夫碱配体的放射性镓配合物可以作为参与肿瘤多药耐药性的MDR1P-糖蛋白(MDR1Pgp)转运的底物。这样的镓放射性药物有望用于PET研究，以量化体内肿瘤MDRI PGP的运输功能。因此，本项目的具体目标是：1.放射性药物的设计与合成；2.作为MDR1 PGP转运基质的放射性药物体外评价；3.作为MDRI PGP转运基质的放射性药物体内评价。新的线性六齿配体，旨在提供一个N4022金属配位球，将被合成用于研究作为MDR1 PGP运输底物的最佳性能的结构-活性关系。体外示踪剂筛选将利用培养的肿瘤细胞来评估药物敏感与耐药细胞的药物选择性、mdr1 Pgp转运动力学和相对mdr1 pgp结合亲和力。用对药物敏感和耐药的裸鼠移植的肿瘤将被用来评估MDRI PGP对放射性药物在体内肿瘤定位的调节。

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.