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

• Published in: Bioorganic & medicinal chemistry Vol. 84; p. 117260
• Main Authors: Suzuki, Chie, Sakai, Toshihiro, Magata, Yasuhiro
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.04.2023; Elsevier
• Subjects: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - chemistry; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Resistance, Neoplasm; Glycoproteins; Humans; Iodine Radioisotopes - chemistry; Iodine Radioisotopes - pharmacology; K562 Cells; Life Sciences & Biomedicine; Membrane Potential, Mitochondrial - physiology; Mitochondrial membrane potential (MMP); P-glycoprotein (P-gp); Pharmacology & Pharmacy; Phosphonium cation; Physical Sciences; Radioligand Assay - methods; Science & Technology; Single photon emission computed tomography (SPECT); Stilbenyl substituent; [18F]FBn-TP; rt; [99mTc]Tc-MIBI; P-gp; [125I]IDPP; Phosphonium cation; ESI-MS; 1H NMR; TLC; Mitochondrial membrane potential (MMP); [125I]IDESP; SPECT; RP-HPLC; ID/g; MMP; SD; P-glycoprotein (P-gp); Stilbenyl substituent; MDR; Single photon emission computed tomography (SPECT); JC-1; CELLS; CYCLOSPORINE-A; RETENTION; Single photon emission computed tomography  RHODAMINE-123
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2023.117260

[Display omitted] 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.