Synthesis and\nEvaluation of <sup>18</sup>F‑Labeled\nPhenylpiperazine-like Dopamine D3 Receptor Radioligands for Positron\nEmission Tomography Imaging

The dopamine D3 receptor (D3R) is important in the pathophysiology\nof various neuropsychiatric disorders, such as depression, bipolar\ndisorder, schizophrenia, drug addiction, and Parkinson’s disease.\nPositron emission tomography (PET) with innovative radioligands provides\nan opportunity to assess D3R in vivo and to elucidate D3R-related\ndisease mechanisms. Herein, we present the synthesis of eight <sup>18</sup>F-labeled phenylpiperazine-like D3R-selective radioligands\npossessing good radiochemical purity (>97%), in vitro stability\n(>95%),\nand befitting lipophilicity. Based on in vitro binding assays and\nstatic microPET studies, the phenylpiperazine-like radioligands [<sup>18</sup>F]FBPC01 and [<sup>18</sup>F]FBPC03 were chosen as lead radioligands\ntargeting D3R. Molecular docking further elucidated their binding\nmechanism. Radiolabeling conditions were optimized and then applied\nto an automated radiolabeling process, affording products with high\nspecific activity (>112 GBq/μmol). Dynamic rat PET study\ndemonstrated\nthe specific binding of [<sup>18</sup>F]FBPC01 and [<sup>18</sup>F]FBPC03\nto D3R in the brain ventricles and the pituitary gland. Validated\nby dynamic PET data analysis, biodistribution study, and metabolism\nanalysis, [<sup>18</sup>F]FBPC03 exhibited the highest PET signal-to-noise\nratio, good D3R-specific binding in the brain ventricles and pituitary\ngland of rats with few off-target binding, negligible defluorination,\nand stable brain metabolism, which indicated that [<sup>18</sup>F]FBPC03\nwas a promising D3R radioligand.