One of the mechanisms of tumor cells to escape the cytotoxic effects of chemotherapeutic agents, such as adriamycin, vinca alkaloids, epipodophyllotoxins, actinomycin D, and paclitaxel, is to limit their presence inside the cells by way of a multidrug resistance (MDR-1) protein (1, 2). The MDR-1 gene encodes a transmembrane P-glycoprotein (P-gp) as an ATP-dependent multidrug transporter that is capable of actively pumping a variety of agents out of the cells. Injection of unlabeled efflux pump substrates increases the retention of the radioactivity in the tumor by blocking the efflux rather than reducing radioactivity uptake as seen with receptor-binding radiotracer blocking studies. Overexpression of P-gp in tumor cells (such as renal carcinoma, hepatoma, pheochromocytoma, and colon carcinoma) leads to resistance to anticancer drugs (3). P-gp is also present in a variety of normal cells, such as intestinal mucosal cells, hepatocytes, renal proximal tubule epithelial cells, and endothelial cells of the blood–brain barrier (BBB) (4, 5). Calcium channel blockers (such as verapamil), cyclosporine (CsA, P-gp inhibitor) and CsA's non-immunosuppressive analog PSC 833 (other mechanism) are MDR modulators that inhibit the transport of P-gp substrates out of the cells (6, 7).
99mTc-Sestamibi (MIBI) has been approved by the United States Food and Drug Administration as a myocardial perfusion imaging agent for use with single-photon emission computed tomography to assess the risk of future cardiac events (8). It is also used as a tumor-imaging agent in breast, lung, thyroid, and brain cancers (8-10). MIBI is a substrate for P-gp (4, 11). 6,7-Dimethoxy-2-{3-[4-methoxy-3,4-dihydro-2H-naphthalen-(1E)-ylidene]-propyl}-1,2,3,4-tetrahydro-isoquinoline (compound 6) is a P-gp inhibitor (12). 6,7-Dimethoxy-2-{3-[4-[11C]methoxy-3,4-dihydro-2H-naphthalen-(1E)-ylidene]-propyl}-1,2,3,4-tetrahydro-isoquinoline ([11C]6) is being developed as a positron emission tomography (PET) agent for the non-invasive study of the P-gp function and MDR in tumors and normal tissues (13).