Reduced P-glycoprotein recognition of a radioiodine-labeled phosphonium cation by stilbenylation for mitochondrial membrane potential based-imaging

Abstract

The accumulation of radiolabeled phosphonium cations in cells is dependent on the mitochondrial membrane potential (MMP). However, the efflux of these cations from tumor cells via P-glycoprotein (P-gp) limits their clinical application as MMP-based imaging tracers. In the present study, we designed (E)-diethyl-4-[¹²⁵I]iodobenzyl-4-stilbenylphosphonium ([¹²⁵I]IDESP), which contains a stilbenyl substituent, as a P-gp inhibitor to reduce P-gp recognition, and evaluated its biological properties in comparison with 4-[¹²⁵I]iodobenzyl dipropylphenylphosphonium ([¹²⁵I]IDPP). The in vitro cellular uptake ratio of [¹²⁵I]IDESP in P-gp expressing K562/Vin cells to the parent (P-gp negative) K562 cells was significantly higher than that of [¹²⁵I]IDPP. The efflux rate of [¹²⁵I]IDESP was not significantly different between K562 and K562/Vin, while [¹²⁵I]IDPP was rapidly effluxed from K562/Vin compared with K562, and the efflux of [¹²⁵I]IDPP from K562/Vin was inhibited by the P-gp inhibitor, cyclosporine A. The cellular uptake of [¹²⁵I]IDESP was well correlated with the MMP levels. These results suggested that [¹²⁵I]IDESP was accumulated in cells depending on the MMP levels, without being effluxed via P-gp, while [¹²⁵I]IDPP was rapidly effluxed from the cells via P-gp. Despite having suitable in vitro properties for MMP-based imaging, [¹²⁵I]IDESP showed rapid blood clearance and lower tumor accumulation than [¹²⁵I]IDPP. Improvement in the normal tissue distribution of [¹²⁵I]IDESP is required to develop an agent for use in in vivo MMP-based tumor imaging.

Keywords: Mitochondrial membrane potential (MMP); P-glycoprotein (P-gp); Phosphonium cation; Single photon emission computed tomography (SPECT); Stilbenyl substituent.