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 Ki = 3.6 nM, increased subtype selectivity (Ki(D2/D3) = 60), and low affinity to 5‐HT1A and α1 receptors (Ki (5‐HT1A/D3) = 34; Ki (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. The optimized reaction of [18F]fluorophenylazocarboxylic tert‐butylester with an amine was applied to the radiosynthesis of [18F]3, achieving an overall non‐decay corrected radiochemical yield of 8–12% and a specific activity of 32–102 GBq/μmol after a total synthesis time of 35 min. The hydroxylated phenylazacarboxamide [18F]3 showed nanomolar affinity for the dopamine D3 receptor and a subtype selectivity of > 6‐fold, providing a D3 radioligand candidate with improved attributes and a reliable and easy radiosynthesis to facilitate further preclinical studies.