Reduced P-glycoprotein recognition of a radioiodine-labeled phosphonium cation by stilbenylation for mitochondrial membrane potential based-imaging. (15th April 2023)

• Record Type: Journal Article
• Authors: Suzuki, Chie; Sakai, Toshihiro; Magata, Yasuhiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 84(2023)
• Publication Date: 2023-04-15
• Subjects: Single photon emission computed tomography (SPECT) -- Mitochondrial membrane potential (MMP) -- Phosphonium cation -- Stilbenyl substituent -- P-glycoprotein (P-gp); ESI-MS electronspray ionization mass spectrometry -- [18F]FBn-TP [18F]fluorobenzyl triphenylphosphine -- 1H NMR proton nuclear magnetic resonance -- [125I]IDESP (E)-diethyl-4-[125I]iodobenzyl-4-stilbenylphosphonium -- %ID/g percentage of injected dose per weight -- [125I]IDPP 4-[125I]iodobenzyldipropylphenylphosphonium -- JC-1 5, 5′, 6, 6′ -tetrachloro-1, 1′, 3, 3′ -tetraethylbenzimidazolocarbocyanine iodide -- MDR multi-drug resistance -- MMP mitochondrial membrane potential -- P-gp P-glycoprotein -- RP-HPLC reversed-phase high-performance liquid chromatography -- rt room temperature -- SD standard deviation -- SPECT single photon emission computed tomography -- [99mTc]Tc-MIBI [99mTc]technetium-methoxyisobutylisonitrile -- TLC thin layer chromatography; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117260
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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-[ 125 I]iodobenzyl-4-stilbenylphosphonium ([ 125 I]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-[ 125 I]iodobenzyl dipropylphenylphosphonium ([ 125 I]IDPP). The in vitro cellular uptake ratio of [ 125 I]IDESP in P-gp expressing K562/Vin cells to the parent (P-gp negative) K562 cells was significantly higher than that of [ 125 I]IDPP. The efflux rate of [ 125 I]IDESP was not significantly different between K562 and K562/Vin, while [ 125 I]IDPP was rapidly effluxed from K562/Vin compared with K562, and the efflux of [ 125 I]IDPP from K562/Vin was inhibited by the P-gp inhibitor, cyclosporine A. The cellular uptake of [ 125 I]IDESP was well correlated with the MMP levels. These results suggested that [ 125 I]IDESP was accumulated in cells depending on the MMP levels, without being effluxed via P-gp, while [ 125 I]IDPP was rapidly effluxed from the cells via P-gp. Despite having suitable in vitro properties for MMP-based imaging, [ 125 I]IDESP showed rapid blood clearance and lower tumor accumulation than [ 125 I]IDPP. Improvement in the normal tissue distribution of [ 125 I]IDESP is required to develop an agent for use in in vivo MMP-based tumor imaging.