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.
