کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1359697 | 981410 | 2011 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Synthesis and in vivo evaluation of 18F-fluoroethyl GF120918 and XR9576 as positron emission tomography probes for assessing the function of drug efflux transporters Synthesis and in vivo evaluation of 18F-fluoroethyl GF120918 and XR9576 as positron emission tomography probes for assessing the function of drug efflux transporters](/preview/png/1359697.png)
The purpose of this study was to synthesize two new positron emission tomography (PET) probes, N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-[18F]fluoroethoxy-9-oxo-4-acridine carboxamide ([18F]3) and quinoline-3-carboxylic acid [2-(4-{2-[7-(2-[18F]fluoroethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethyl}phenylcarbamoyl)-4,5-dimethoxyphenyl]amide ([18F]4), and to evaluate the potential of these PET probes for assessing the function of two major drug efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). [18F]3 and [18F]4 were synthesized by 18F-alkylation of each O-desmethyl precursor with [18F]2-fluoroethyl bromide for injection as PET probes. In vitro accumulation assay showed that treatment with P-gp/BCRP inhibitors (1 and 2) enhanced the intracellular accumulation capacity of P-gp- and BCRP-overexpressing MES-SA/Dx5 cells. In PET studies, the uptake (AUCbrain [0–60 min]) of [18F]3 and [18F]4 in wild-type mice co-injected with 1 were approximately sevenfold higher than that in wild-type mice, and the uptake of [18F]3 and [18F]4 in P-gp/Bcrp knockout mice were eight- to ninefold higher than that in wild-type mice. The increased uptake of [18F]3 and [18F]4 was similar to that of parent compounds ([11C]1 and [11C]2) previously described, indicating that radioactivity levels in the brain after injection of [18F]3 and [18F]4 are related to the function of drug efflux transporters. Also, these results suggest that the structural difference between parent compounds ([11C]1 and [11C]2) and fluoroethyl analogs ([18F]3 and [18F]4) do not obviously affect the potency against drug efflux transporters. In metabolite analysis of mice, the unchanged form in the brain and plasma at 60 min after co-injection of [18F]4 plus 1 were higher (95% for brain; 81% for plasma) than that after co-injection of [18F]3 plus 1. [18F]4 is a promising PET probe to assess the function of drug efflux transporters.
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Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 2, 15 January 2011, Pages 861–870