Design, Synthesis, Lipophilic Properties, and Binding Affinities of Potential Ligands in Positron Emission Tomography (PET) for Visualization of Brain Dopamine D-4 Receptors

作者：Lacivita Enza; De Giorgio Paola; Colabufo Nicola A; Berardi Francesco; Perrone Roberto; Niso Mauro; Leopoldo Marcello^*

来源：Chemistry and Biodiversity, 2014, 11(2): 299-310.

DOI：10.1002/cbdv.201300194

• Dopamine D4 receptors
• Structure Symbol of the Klingon Empire activity relationships (SAR)
• cLogP
• Piperazine, 1-aryl-
• Positron Emission Tomography (PET)
• G-Protein-coupled receptors (GPCR)

We report the synthesis of compounds structurally related to the high-affinity dopamine D-4 receptor ligand N-{2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-methoxybenzamide (1e). All compounds were specifically designed as potential PET radioligands for brain D-4 receptor visualization, having lipophilicity within a range for brain uptake and weak non-specific binding (0.75P<3.15) and bearing a substituent for easy access to labeling with the positron emitter isotope C-11 or F-18. The best compound of the series, N-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-6-fluoropyridine-3-carboxamide (7a), displayed excellent selectivity over D-2 and D-3 receptors (>100-fold), but its D-4 receptor affinity was suboptimal for imaging of brain D-4 receptors (K-i=30 nM).

• 出版日期2014-2