Assessment of the in vitro and in vivo properties of a Tc-99m-labeled inhibitor of the multidrug resistant gene product P-glycoprotein

Overexpression of P-glycoprotein (Pgp), which is present in the plasma memb rane of various tumor cells and in several normal cell types, contributes t o the multidrug resistance (MDR) phenotype of many human cancers. As a prer equisite for therapy, the expression of Pgp must be studied. The available clinical radiopharmaceuticals for studying the expression of Pgp include th e lipophilic Tc-99m cations (sestamibi, tetrofosmin) as well as [Tc-99m]Q57 , [Tc-99m]Q58, and [Tc-99m]Q63. Here we describe the in vitro and in vivo p roperties of the structurally different complex (3-thiapentane-1,5-dithiola to){[N-(3-phenylpropyl)-N-2(3-quinazoline-2,4 -dionyl)-ethyl]amino-ethylthi olato} oxotechnetium(V) ((99/99m)Tc1) as a potential inhibitor of Pgp. (99) Tc1 enhances the net cell accumulation of Pgp substrates [H-3]vinblastine, [H-3]vincristine, [H-3]colchicine, [Tc-99m]sestamibi, and [Tc-99m]tetrofosm in in rat brain endotheliat cells (RBE4), an immortalized endothelial cell line that expresses Pgp. In addition, the cell accumulation of (99m)Tc1 cou ld be increased by verapamil and reserpine, which are known Pgp inhibitors. A multitracer approach was used to study the side effects of (99)Tc1 on ce ll metabolism. The cells were simultaneously incubated with [Tc-99m]sestami bi, 2-[F-18]fluoro-2-deoxyglucose ([F-18]FDG), and various H-3-labeled trac ers. Two-dimensional scatter plots of [Tc-99m]sestamibi uptake/[F-18]FDG up take show typical changes of known Pgp inhibitors including (99)Tc1. The ef fects of (99)Tc1 on the in vivo distribution of [Tc-99m]sestamibi and [F-18 ]FDG in rats also are comparable with the effects of verapamil, an establis hed Pgp inhibitor and calcium channel blocker. We conclude that (99/99m)Tc1 is a transport substrate and a potential inhibitor of Pgp. Our approach ma y be useful in the design of further radiotracers with specificity to Pgp. NUCL MED BIOL 27;2:135-141, 2000. (C) 2000 Elsevier Science Inc. All rights reserved.