Synthesis and pre-clinical evaluation of a potential radiotracer for PET imaging of the dopamine D3 receptor

Abstract

There is considerable interest in using positron emission tomography (PET) imaging to understand the function of dopamine D₃ receptors. Due to high sequence homology with D₂ receptors, development of D₃-selective PET radiotracers has been challenging. In an effort to overcome this issue, we report the radiosynthesis of a new selective D₃ ligand with carbon-11 ([¹¹C]1), and its initial preclincial evaluation as a potential PET radiotracer for in vivo imaging of D₃ receptors. [¹¹C]1 was prepared via [¹¹C]CO₂ fixation in 0.1% non-corrected radiochemical yield, good radiochemical purity (>95%) and high specific activity (>2000 Ci mmol⁻¹). [¹¹C]1 exhibited specific binding to D₃ receptors using ex vivo autoradiography experiments with rat brain, but only 14-fold selectivity over D₂ receptors which is lower than the 1400-fold value reported previously for cell studies. Rodent PET imaging revealed reasonable uptake of the radiotracer in areas of the brain known to be rich in D₃ receptors.