Synthesis and biological evaluation of ¹⁸F-labelled dopamine D₃ receptor selective ligands

The dopamine D₃ receptor (D₃R) is highly expressed in the limbic regions of the brain and closely related to a variety of neurological disorders including Parkinson's disease, schizophrenia and drug-seeking behavior. In vivo imaging of D₃R with radio-labelled tracers and positron emission tomography (PET) has become a powerful technique in related disorders. In this study, we synthesized three novel aromatically ¹⁸F-labelled phenylpiperazine-like D₃R selective radioactive ligands ([¹⁸F]5b, [¹⁸F]8b and [¹⁸F]11b) and developed a simple, rapid and efficient ¹⁸F-labelling method by condition optimization. Radiosynthesis of [¹⁸F]5b, [¹⁸F]8b and [¹⁸F]11b was achieved by ¹⁸F-fluorination from nitroarene precursors. Final radiochemical purities of [¹⁸F]5b, [¹⁸F]8b and [¹⁸F]11b solution were > 99% and remained good stability (> 98% for up to 6 h) in PBS and FBS. PET imaging and cellular binding studies revealed that [¹⁸F]8b had a higher D₃R affinity than [¹⁸F]5b and [¹⁸F]11b. Autoradiography and biodistribution studies of the brain showed that [¹⁸F]8b had medium intensity specific accumulation in the striatum and cortex. Meanwhile, the low skeletal uptake of [¹⁸F]8b revealed a good in vivo stability with negligible defluorination. These results indicated that [¹⁸F]8b might be a potential ¹⁸F-labelled D₃R PET imaging agent.