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

Abstract

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.