Multidrug resistance (MDR) mediated by overexpression of MDR1 P-glycoprotein (Pgp) is one of the best characterized barriers to chemotherapy in cancer patients. Furthermore, the protective function of Pgp-mediated efflux of xenobiotics in various organs has a profound effect on the bioavailability of drugs in general. Thus, there is an expanding requirement to noninvasively interrogate Pgp transport activity in vivo. We herein report the Pgp recognition properties of a novel 99mTc(I)-tricarbonyl complex, [99mTc(CO)3(MIBI)3]+ (Tc-CO-MIBI). Tc-CO-MIBI showed 60-fold higher accumulation in drug-sensitive KB 3-1 cells compared to colchicine-selected drug-resistant KB 8-5 cells. In KB 8-5 cells, tracer enhancement was observed with the potent MDR modulator LY335979 (EC50 = 62 nM). Similar behavior was observed using drug-sensitive MCF-7 breast adenocarcinoma cells and MCF-7/MDR1 stable transfectants, confirming that Tc-CO-MIBI is specifically excluded by overexpression of MDR1 Pgp. By comparison, net accumulation in control H69 lung tumor cells was 9-fold higher than in MDR-associated protein (MRP1)-expressing H69AR cells, indicating only modest transport by MRP1. Biodistribution analysis following tail vein injection of Tc-CO-MIBI showed delayed liver clearance as well as enhanced brain uptake and retention in mdr1a/1b(-/-) gene deleted mice versus wild-type mice, directly demonstrating that Tc-CO-MIBI is a functional probe of Pgp transport activity in vivo.

Multidrug resistance (MDR) mediated by overexpression of MDR1 P-glycoprotein (Pgp) is one of the best characterized barriers to chemotherapy in cancer patients. Furthermore, the protective function of Pgp-mediated efflux of xenobiotics in various organs has a profound effect on the bioavailability of drugs in general. Thus, there is an expanding requirement to noninvasively interrogate Pgp transport activity in vivo. We herein report the Pgp recognition properties of a novel

One of the best characterized mechanisms of drug resistance in human tumors is overexpression of the multidrug resistance (MDR1) P‐glycoprotein (Pgp). Pgp functions as an energy‐dependent extrusion pump that efficiently transports drugs out of tumor cells and has thus been an attractive target for improving cancer therapies (1). Lipophilic cationic radiopharmaceuticals, such as 99mTc‐sestamibi and 99mTc‐tetrofosmin, have been validated as transport substrates for Pgp in a variety of multidrug resistant human and rodent cells and have demonstrated utility for functional imaging of Pgp transport and modulation in both normal human tissues and tumors as well as in FVB mdrla/lb(‐l‐) gene knockout mice (2–7). The aim of this study was to explore the Pgp recognition properties of novel 99mTc(I)‐tricarbonyl complexes containing either methoxyisobutylisonitrile (MIBI) or dimethylmethoxypropylphosphine (DMMPP) ligands that have recently been reported as potential cardiac imaging agents (8).