Synthesis and Evaluation of 18F‑Labeled Phenylpiperazine-like Dopamine D3 Receptor Radioligands for Positron Emission Tomography Imaging

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