Imaging of activity of multidrug resistance-associated protein 1 in the lungs.

Multidrug resistance-associated protein 1 (MRP1) transports various xenobiotics and metabolites across cell membranes, and the alteration of MRP1 expression is associated with certain lung diseases. This study sought to examine the feasibility of imaging pulmonary MRP1 activity using 6-bromo-7-[(11)C]methylpurine ([(11)C]1). A positron emission tomography study with [(11)C]1 was performed in wild-type, Mrp1 knockout (KO), and P-glycoprotein/breast cancer resistance protein (Pgp/Bcrp) KO mice. Lung radioactivity in wild-type and Mrp1 KO mice reached a maximum level immediately after the administration of [(11)C]1. Thereafter, radioactivity rapidly decreased in the lungs of wild-type mice, whereas it was mostly retained in the lungs of Mrp1 KO mice. The kinetics in the lungs of Pgp/Bcrp KO mice was quite similar to that of wild-type mice. Analysis of the chemical form confirmed that radioactive compounds in the lungs of Mrp1 KO mice were nearly completely composed of a glutathione conjugate, a MRP1 substrate, 5 minutes after the intravenous administration of [(11)C]1. The effect of an MRP1 inhibitor, MK571, on the kinetics of [(11)C]1 was also examined. Treatment with MK571 delayed the elimination of radioactivity from the lungs, compared with control mice. These results suggest that [(11)C]1 diffuses into the lung tissue after administration and undergoes conversion into the hydrophilic conjugate, which is then specifically expelled by MRP1. In conclusion, [(11)C]1 allows for the imaging of in vivo MRP1 activity in lungs.