Design,Synthesis,and Binding Affinities of Potential Positron Emission Tomography (PET) Ligands for Visualization of Brain Dopamine D_3 Receptors

摘要

We here report the synthesis of compounds structurally related to the high-affinity dopamine D_3 receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (1).All compounds were specifically designed as potential PET radioligands for brain D_3 receptors visualization,having lipophilicity within a range for high brain uptake and weak nonspecific binding (2 < ClogP < 3.5) and bearing a methoxy substituent for easy access to labeling with the positron emitter isotope ~(11)C.N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(4-morpholinyl)benzamide (22),N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(lH-imidazol-1-yl)benzamide (23),and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-5-(2-furanyl)-lH-pyrazole-3-carboxamide (24) displayed good D_3 receptor affinities (K_i values 38.0,22.6,and 21.3 nM,respectively) and were selective over D_2 receptor.Moreover,compounds 22-24 were able to permeate the Caco-2 cell monolayer,differently from compound 1.Although the goal to identify potential PET radioligands with subnanomolar affinities for D_3 receptor was not achieved,the proposed strategy could be a starting point for future developments.