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

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 D4 receptor imaging agents by positron emission tomography (PET). Binding affinities of these ligands for the dopamine D2, D3, and D4 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. 18F-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.