Evaluation of 18F-Labeled Benzodioxine Piperazine-Based Dopamine D4 Receptor Ligands: Lipophilicity as a Determinate of Nonspecific Binding

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• 作者：Fabian K眉gler ; Wiebke Sihver ; Johannes Ermert ; Harald H眉bner ; Peter Gmeiner ; Olaf Prante ; Heinz H. Coenen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8343-8352
• 全文大小：404K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

Derivatization of the putative neuroleptic 1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-(4-fluorobenzyl)piperazine (3a) led to a series of new dopamine receptor D₄ ligands displaying high affinity (K_i = 1.1鈥?5 nM) and D₂/D₄ subtype selectivities of about 800鈥?700. These ligands were labeled with the short-lived positron emitter fluorine-18 and analyzed for their potential application for imaging studies by positron emission tomography (PET). In vitro autoradiography was used to determine their nonspecific binding behavior as a result of their structural and thus physicochemical properties. The biodistribution, in vivo stability, and brain uptake of the most promising D₄ radioligand candidate were determined. This proved to be 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-((6-fluoropyridin-3-yl)methyl)piperazine ([¹⁸F]3d), which revealed an excellent binding pattern with a high selectivity and limited nonspecific binding in vitro. This analogue also exhibited a high stability and an extremely high brain uptake in vivo with specific binding in hippocampus, cortex, colliculus, and cerebellum as determined by ex vivo autoradiography. Thus, [¹⁸F]3d appears as a suitable D₄ radioligand for in vivo imaging, encouraging continued evaluation by PET studies.