Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET

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• 作者：Olaf Prante ; Rainer Tietze ; Carsten Hocke ; Stefan Lö ; ber ; Harald H&#xfc ; bner ; Torsten Kuwert ; Peter Gmeiner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1800 - 1810
• 全文大小：531K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5-a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D₄ receptor (D₄R) ligands (3a−3h, K_i = 1.3–28 nM). The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D₄ subtype selectivity of more than 3 orders of magnitude over both congeners D₂ and D₃ combined with inverse agonism at D₄R. The corresponding ¹⁸F-labeled radioligands revealed high serum stability in vitro and log P values of 2–3. In vitro rat brain autoradiography showed specific binding of [¹⁸F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65–80%) and the selective D₄R antagonist 10 (78–93%). The observed binding pattern was mainly consistent with the known D₄R distribution in the rat brain. Thus, [¹⁸F]3h (FAUC F41) represents a potential radioligand for studying the D₄R in vivo by positron emission tomography (PET).