[³H]BMS-599240 — A novel tritiated ligand for the characterization of BACE1 inhibitors

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• 作者：Lawrence G. Iben ; Lisa Kopcho ; Jovita Marcinkeviciene ; Changsheng Zheng ; Lorin A. Thompson ; Charles F. Albright ; Jeremy H. Toyn
• 关键词：Alzheimer disease ; β ; -amyloid precursor protein ; BACE ; BMS-599240 ; Radioligand ; β ; -Secretase
• 刊名：European Journal of Pharmacology
• 出版年：2008
• 出版时间：28 September 2008
• 年：2008
• 卷：593
• 期：1-3
• 页码：10-15
• 全文大小：323 K

文摘

In this report we describe a novel radioligand, [³H](S)-2-((S)-3-Acetylamino-3-sec-butyl-2-oxo-pyrrolidin-1-yl)-N-[(1S,2R)-1-benzyl-2-hydroxy-3-(3-methoxy-benzylamino)-propyl]-4-phenyl-butyramide ([³H]BMS-599240), that exhibits robust specific binding in homogenates from cell cultures overexpressing β-site amyloid precursor protein cleaving enzyme-1 (BACE1). Radioligand binding exhibited high affinity, K_d = 2 nM, commensurate with its inhibitory potency against BACE1. Inhibition of radioligand binding in the presence of a range of different BACE1 inhibitors exhibited the same rank order of potency as for inhibition of BACE1 enzymatic activity. BACE1-dependent binding of the radioligand was also demonstrated in mouse brain homogenates, where genetic ablation of BACE1 eliminated high affinity binding. Thus, the radioligand [³H]BMS-599240 is a novel tool potentially useful for evaluation of BACE1 enzyme in biological samples, and for evaluation of inhibitor binding to BACE1.