Reactivity of 6-Halopurine Analogs with Glutathione as a Radiotracer for Assessing Function of Multidrug Resistance-Associated Protein 1

6-Bromo-7-[11C]methylpurine is reported to react with glutathione via glutathione S-transferases in the brain and to be converted into a substrate for multidrug resistance-associated protein 1 (MRP1), an efflux pump. The compound with a rapid conversion rate allows quantitative assessment of MRP1 fu...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2009-11, Vol.52 (22), p.7284-7288
Main Authors: Okamura, Toshimitsu, Kikuchi, Tatsuya, Fukushi, Kiyoshi, Irie, Toshiaki
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Brain - diagnostic imaging
Brain - metabolism
Drug Design
Glutathione - metabolism
Humans
Hydrophobic and Hydrophilic Interactions
Isomerism
Kinetics
Male
Medical sciences
Mice
Miscellaneous
Multidrug Resistance-Associated Proteins - metabolism
Pharmacology. Drug treatments
Positron-Emission Tomography
Protein Binding
Purines - chemistry
Purines - metabolism
Radioactive Tracers
Rats
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:6-Bromo-7-[11C]methylpurine is reported to react with glutathione via glutathione S-transferases in the brain and to be converted into a substrate for multidrug resistance-associated protein 1 (MRP1), an efflux pump. The compound with a rapid conversion rate allows quantitative assessment of MRP1 function, but this rate is probably susceptible to interspecies differences. Hence, for application to different species, including humans, it is necessary to adjust the conversion rate by modifying the chemical structure. We therefore designed 6-halo-9-(or 7)-[ 14C]methylpurine (halogen: F, Cl, Br, or I), and evaluated them in vitro with respect to enzymatic reactivity with glutathione using brain homogenates from the mouse, rat, or monkey. There was a marked difference in reactivity between these species. Changes in the position of the methyl group and halogen on N-methyl-6-halopurine provided various compounds possessing wide-ranging reactivity with glutathione. In conclusion, the adjustment of reactivity of 6-bromo-7-[11C]methylpurine may allow assessment of MRP1 function in the brain in various species.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm901332c