Optimization and synthesis of an 18F‐labeled dopamine D3 receptor ligand using [18F]fluorophenylazocarboxylic tert‐butylester

There is still no efficient fluorine‐18‐labeled dopamine D₃ subtype selective receptor ligand for studies with positron emission tomography. We aim at improving the D₃ selectivity and hydrophilicity of a candidate ligand by changing the substitution pattern to a 2,3‐dichlorophenylpiperazine and hydroxylation of the butyl chain. The compound ¹⁸F]3 exhibited D₃ affinity of K_i = 3.6 nM, increased subtype selectivity (K_i(D₂/D₃) = 60), and low affinity to 5‐HT_1A and α₁ receptors (K_i (5‐HT_1A/D₃) = 34; K_i (α₁/D₃) = 100). The two‐step radiosynthesis was optimized for analog ¹⁸F]4 by reducing the necessary concentration of the precursor amine (57 mM), which reacted with ¹⁸F]fluorophenylazocarboxylic tert‐butylester under basic conditions. The optimization of the base (Cs ₂CO₃, 23 mM) and the adjustment of reaction temperature led to the radiochemical yield of 63% after 5 min at 35°C. The optimized reaction conditions were transferred on to the synthesis of ¹⁸F]3 with an overall non‐decay corrected yield of 8‐12% in a specific activity of 32‐102 GBq/µmol after a total synthesis time of 30‐35 min. This provides a D ₃ radioligand candidate with improved attributes concerning selectivity and radiosynthesis for further preclinical studies.