Synthesis, 18F-Radiolabeling, and in Vivo Biodistribution Studies of N-Fluorohydroxybutyl Isatin Sulfonamides using Positron Emission Tomography

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• 作者：Panupun Limpachayaporn ; Stefan Wagner ; Klaus Kopka ; Sven Hermann ; Michael Sch盲fers ; G眉nter Haufe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4509-4520
• 全文大小：535K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

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-[¹⁸F]fluoro-3(R)-hydroxybutyl)- and N-(3(S)-[¹⁸F]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鈥?27 GBq/渭mol using [¹⁸F]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.