Design, Synthesis, Lipophilic Properties, and Binding Affinities of Potential Ligands in Positron Emission Tomography (PET) for Visualization of Brain Dopamine D4 Receptors. Issue 2 (February 2014) - Lacivita, Enza
Abstract We report the synthesis of compounds structurally related to the high‐affinity dopamine D4 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 D4 receptor visualization, having lipophilicity within a range for brain uptake and weak non‐specific binding (0.75<cLogP<3.15) and bearing a substituent for easy access to labeling with the positron emitter isotope 11C or 18F. The best compound of the series, N‐{2‐[4‐(4‐chlorophenyl)piperazin‐1‐yl]ethyl}‐6‐fluoropyridine‐3‐carboxamide (7a), displayed excellent selectivity over D2 and D3 receptors (>100‐fold), but its D4 receptor affinity was suboptimal for imaging of brain D4 receptors (Ki=30 nM).