Journal of labelled compounds and radiopharmaceuticals p. 48 - 53 (2016)
Update date:2022-08-30
Topics:
Nebel, Natascha
Maschauer, Simone
Hocke, Carsten
Hübner, Harald
Gmeiner, Peter
Prante, Olaf
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 35C. 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.
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