Radiofluorinated histamine H₃ receptor antagonist as a potential probe for in vivo PET imaging: Radiosynthesis and pharmacological evaluation

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• 作者：Svetlana V. Selivanova^a ; ^{svetlana.selivanova@pharma.ethz.ch} ; Michael Honer^a ; Francine Combe^a ; Kathleen Isensee^b ; Holger Stark^b ; Stefanie D. Krä ; mer^a ; P. August Schubiger^a ; Simon M. Ametamey^a
• 关键词：H3R ; histamine H3 receptor ; CNS ; central nervous system ; GPCRs ; G-protein coupled receptors ; BBB ; blood&ndash ; brain barrier ; CYP ; cytochrome-P450 ; P-gp ; P-glycoprotein ; PET ; positron emission tomography ; EOB ; end of bombardment ; EOS ; end of synthesis ; HPL
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 May, 2012
• 卷：20
• 期：9
• 页码：2889-2896
• 文件大小：528 K

摘要

The histamine H₃ receptor (H₃R) plays a role in cognition and memory processes and is implicated in different neurological disorders, including Alzheimer鈥檚 disease, schizophrenia, and narcolepsy. In vivo studies of the H₃R occupancy using a radiolabeled PET tracer would be very useful for CNS drug discovery and development. We report here the radiosynthesis, in vitro and in vivo evaluation of a novel ¹⁸F-labeled high-affinity H₃R antagonist ¹⁸F-ST889. The radiosynthesis was accomplished via nucleophilic substitution of the mesylate leaving group with a radiochemical yield of 8-20%, radiochemical purity >99%, and specific radioactivity >65 GBq/渭mol. ¹⁸F-ST889 exhibited high in vivo stability and rather low lipophilicity (log D_7.4 = 0.35 卤 0.09). In vitro autoradiography showed specific binding in H₃R-rich brain regions such as striatum and cortex. However, in vivo PET imaging of the rat brain with ¹⁸F-ST889 was not successful. Possible reasons are discussed.