Reduced P-glycoprotein recognition of a radioiodine-labeled phosphonium cation by stilbenylation for mitochondrial membrane potential based-imaging.
Bioorg Med Chem
; 84: 117260, 2023 04 15.
Article
in En
| MEDLINE
| ID: mdl-37003156
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
ATP Binding Cassette Transporter, Subfamily B, Member 1
/
Membrane Potential, Mitochondrial
/
Iodine Radioisotopes
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2023
Type:
Article
Affiliation country:
Japan