Design synthesis, and binding affinity of potential positron emission tomography (PET) ligands for visualitation of brain dopamine D3 receptors

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-(1H-imidazol-1-yl)benzamide (23), and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-5-(2-furanyl)-1H-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.