Design, Synthesis, and Binding Affinities of Potential Positron Emission Tomography (PET) Ligands for Visualization of Brain Dopamine D3 Receptors
| Autor: | Marcello Leopoldo, Roberto Perrone, Francesco Berardi, Mauro Niso, Paola De Giorgio, Nicola Antonio Colabufo, Enza Lacivita |
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| Rok vydání: | 2005 |
| Předmět: |
Stereochemistry
Ligands Chemical synthesis Piperazines Structure-Activity Relationship chemistry.chemical_compound Dopamine receptor D3 Dopamine receptor D2 Drug Discovery Animals Humans Benzamide Receptor Benzofurans Molecular Structure Chemistry Ligand Receptors Dopamine D3 Brain Affinities Rats Drug Design Positron-Emission Tomography Lipophilicity Molecular Medicine Caco-2 Cells Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 49:358-365 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm050734s |
| Popis: | 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 (2ClogP3.5) 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. |
| Databáze: | OpenAIRE |
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