Assessment of the in vitro and in vivo properties of a ^99mTc-labeled inhibitor of the multidrug resistant gene product P-glycoprotein.

Overexpression of the P-glycoprotein (Pgp), present in the plasma membrane of various tumour cells and in several normal cell types contributes to the multiple drug resistance (MDR) phenotype of many human cancers. As an prerequisite for the therapy it is required to study the expression of Pgp. The available clinical radiopharmaceuticals to study the expression of Pgp include the lipophilic ^99mTc cations (sestamibi, tetrofosmin) as well as [^99mTc]Q57, [^99mTc]Q58, and [^99mTc]Q63. Here we describe the in vitro and in vivo properties of the structurally different complex (3-thiapentane-1,5-dithiolato){[N-(3-phenylpropyl)-N-2(3-quinazoline-2,4-dionyl)-ethyl]amino-ethylthiolato}oxotechnetium(V) (^99/99mTc1) as a potential inhibitor of the Pgp. ⁹⁹Tc1 enhances the net cell accumulation of the Pgp substrates [³H]vinblastine, [³H]vincristine, [³H]colchicine, [^99mTc]sestamibi, [^99mTc]tetrofosmin in RBE4 cells, an immortalised endothelial cell line which expresses Pgp. Also, the cell accumulation of ^99mTc1 could be increased by verapamil and reserpine as known Pgp inhibitors. A multitracer approach was used to study the side effects of ⁹⁹Tc1 on cell metabolism. The cells were simultaneously incubated with [^99mTc]sestamibi, [¹⁸F]FDG and various ³H-labelled tracers. Two-dimensional scatter plots of [^99mTc]sestamibi uptake / [¹⁸F]FDG uptake show typical changes of known Pgp inhibitors including ⁹⁹Tc1. Also the effects of the ⁹⁹Tc1 on the in vivo distribution of [^99mTc]sestamibi and [¹⁸F]FDG in rats are comparable with the effects of verapamil, an established Pgp inhibitor and Ca-channel blocker.
We conclude that ^99/99mTc1 is a transport substrate and a potential inhibitor of the Pgp. Our approach may be useful in the design of further radiotracers with specificity to the Pgp.