Synthesis and biological evaluation of potential positron emission tomography (PET) ligands for brain visualization of dopamine D3 receptors

Abstract

Currently, the lack of a selective dopamine D 3 PET (positron emission tomography) radioligand for in vivo brain occupancy studies is problematic. Several requirements are necessary for a potential PET radioligand for visualization of a receptor into the brain: i) high affinity and selectivity for the target receptor; ii) suitable lipophilicity for both blood-brain barrier permeation and low nonspecific binding to proteins and lipids; iii) structural features that allow labelling with a positron emission isotope. In this study the synthesis and binding affinities for dopamine D 3 and D 2 receptors of several N- [4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides are reported. These compounds were designed by the structural modification of the formerly reported D 3 receptor ligand N- [4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (1), with the aim to obtain a suitable lipophilicity and the structural features for labelling. In particular, both the 2,3-dichlorophenyl group and the 7-methoxy-2-benzofurancarboxamide moiety were replaced by less lipophilic fragments. Among the studied compounds, derivatives N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(4-morpholinyl)benzamide (20), N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(1H-imidazol-1-yl)benzamide (21), and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-5-(2-furanyl)-1H-pyrazole-3-carboxamide (22) displayed good D 3 receptor affinities (K i values 38, 22.6, and 21.3 nM, respectively) and were found to be inactive at D 2 receptor. Moreover, on the basis of their experimental log P values and their ability to cross the Caco-2 monolayer, compounds 20-22 are likely to permeate the blood-brain barrier, differently from compound 1.