期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 11, 页码 4509-4520出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm400257a
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资金
- Deutsche Forschungsgemeinschaft (Collaborative Research Center) [SFB 656, B1, A3, C6, Z5]
- International NRW Graduate School of Chemistry, Munster (GSC)
- Interdisciplinary Centre for Clinical Research (core unit PIX), Munster
- Development and Promotion of Science and Technology (DPST) talent project, Thailand
The effector caspases-3 and -7 play a central role in programmed type I cell death (apoptosis). Molecular imaging using positron emission tomography (PET) by tracking the activity of executing caspases might allow the detection of the early onset as well as therapy monitoring of various diseases induced by dysregulated apoptosis. Herein, four new fluorinated diastereo-and enantiopure isatin sulfonamide-based potent and selective caspase-3 and -7 inhibitors were prepared by cyclic sulfate ring-opening with fluoride. All fluorohydrins exhibited excellent in vitro affinities (up to IC50 = 11.8 and 0.951 nM for caspase-3 and -7, respectively), which makes them appropriate PET radiotracer candidates. Therefore, N-(4-[F-18]fluoro-3(R)-hydroxybutyl)and N-(3(S)-[F-18]fluoro-4-hydroxybutyl)-5-[1-(2(S)-(methoxymethyl)pyrrolidinyl)sulfonyl]isatin were synthesized in 140 min with 24% and 10% overall radiochemical yields and specific activities of 10-127 GBq/mu mol using [F-18]fluoride in the presence of Kryptofix and subsequent acidic hydrolysis. In vivo biodistribution studies in wild-type mice using PET/computed tomography imaging proved fast clearance of the tracer after tail vein injection.
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