Design,Synthesis, Lipophilic Properties,and Binding Affinities of Potential Ligands in Positron Emission Tomography (PET) for Visualization of Brain Dopamine D4 Receptors |
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Authors: | Enza Lacivita Paola De?Giorgio Nicola A Colabufo Francesco Berardi Roberto Perrone Mauro Niso Marcello Leopoldo |
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Institution: | 1. Dipartimento di Farmacia?–?Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, IT‐70125, Bari, (phone +39?080?544?2798;2. fax +39?080?544?2231) |
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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 ). |
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Keywords: | Positron Emission Tomography (PET) G‐Protein‐coupled receptors (GPCR) cLogP Structure activity relationships (SAR) Dopamine D4 receptors Piperazine 1‐aryl‐ |
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