title: Optimization and synthesis of an (18) F-labeled dopamine D3 receptor ligand using [(18) F]fluorophenylazocarboxylic tert-butylester.
abstract: 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 [(18) F]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 [(18) F]4 by reducing the necessary concentration of the precursor amine (57 mM), which reacted with [(18) F]fluorophenylazocarboxylic tert-butylester under basic conditions. The optimization of the base (Cs 2 CO3 , 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 [(18) F]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.
authors.affiliation: Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Nebel
authors.affiliation: Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Maschauer
authors.affiliation: Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Hocke
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schuhstrasse 19, D-91052, Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schuhstrasse 19, D-91052, Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
mesh_terms: D000085:Acetates / Q000737:chemistry; D015259:Dopamine Agents / Q000138:chemical synthesis*; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors; D020002:tert-Butyl Alcohol / Q000031:analogs & derivatives
chemical_list: D000085:Acetates; D015259:Dopamine Agents; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D050637:Receptors, Dopamine D3; D020002:tert-Butyl Alcohol; C415326:phenoxyacetic acid
keywords: dopamine D3 receptor; nucleophilic aromatic 18F-fluorination; phenylazocarboxylic esters; positron emission tomography