Synthesis and Evaluation of Novel 伪-Fluorinated (E)-3-((6-Methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyl Oxime (ABP688) Derivatives as Metabotropic Glutamate Receptor Subtype 5 PET

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• 作者：Selena Milicevic Sephton ; Linjing Mu ; W. Bernd Schweizer ; Roger Schibli ; Stefanie D. Kr盲mer ; Simon M. Ametamey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7154-7162
• 全文大小：470K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

In the search for an optimal fluorine-18-labeled positron emission tomography (PET) radiotracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5), we have prepared a series of five 伪-fluorinated derivatives based on the ABP688 structural manifold by application of a two-step enolization/NFSI 伪-fluorination method. Their binding affinities were evaluated in vitro, and the most promising candidate (Z)-16 exhibited a K_i of 5.7 nM and a clogP value of 2.3. The synthesis of the precursor tosylate (E)-22 revealed a preference for the (E)-configurational isomer (K_i = 31.2 nM), and successful radiosynthesis afforded (E)-[¹⁸F]-16 which was used as a model PET tracer to establish plasma and PBS stability. (E)-[¹⁸F]-16 (K_d = 70 nM) exhibited excellent specificity for mGluR5 in autoradiographic studies on horizontal rat brain slices in vitro.