Synthesis and evaluation of fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives for dopamine D4 receptor imaging

Seven fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were synthesized based on a lead ligand, 3-[[4-(4-iodophenyl)piperazin-1-yl]-methyl]-1H-pyrrolo[2,3-b]pyridine (L-750,667) and evaluated as potential dopamine D-4 receptor imaging agents by positron emission tomography (PET). Binding affinities of these ligands for the dopamine D-2, D-3, and D-4 receptor subtypes were measured in vitro. Most ligands showed high and selective binding for the D4 receptor. Ligand 7 had high affinity for the D4 receptor, whereas ligands 1, 2, and 6 showed high selectivity for the D4 receptor. Log P values were calculated for the ligands in this series and ligand 6 had the lowest lipophilicity. F-18-labeled ligand 7 demonstrated a uniform regional brain distribution and a rapid washout in mice, probably due to nonspecific binding. Based on their in vitro binding properties and calculated log P values, ligand 6 appears to have the most promise for dopamine D4 receptor imaging. (C) 2004 Elsevier Ltd. All rights reserved.