title: Reactivity of 6-halopurine analogs with glutathione as a radiotracer for assessing function of multidrug resistance-associated protein 1.
abstract: 6-Bromo-7-[(11)C]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)-[(14)C]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-[(11)C]methylpurine may allow assessment of MRP1 function in the brain in various species.
authors.affiliation: Probe Research Section, Department of Molecular Probe, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Okamura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukushi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Irie
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D015195:Drug Design; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D007700:Kinetics; D008297:Male; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011687:Purines / Q000737:chemistry* / Q000378:metabolism*; D011849:Radioactive Tracers; D051381:Rats
chemical_list: D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011687:Purines; D011849:Radioactive Tracers; C545688:6-bromo-7-methylpurine; C421109:multidrug resistance-associated protein 1