Optimization and synthesis of an (18) F-labeled dopamine D3 receptor ligand using [(18) F]fluorophenylazocarboxylic tert-butylester.
Optimization and synthesis of an (18) F-labeled dopamine D3 receptor ligand using [(18) F]fluorophenylazocarboxylic tert-butylester.
复制标题
DOI：
10.1002/jlcr.3361
复制
发表时间：
2016-02
影响因子：
1.8
通讯作者：
N. Nebel;S. Maschauer;C. Hocke;H. Hübner;P. Gmeiner;O. Prante
中科院分区：
文献类型：
--
作者：
N. Nebel;S. Maschauer;C. Hocke;H. Hübner;P. Gmeiner;O. Prante
仍然没有有效的氟-18标记的多巴胺D3亚型选择性受体配体用于正电子发射断层扫描研究。我们的目标是通过改变取代模式为2，3-二氯苯基哌嗪和丁基链的羟基化来提高候选配体的D3选择性和亲水性。化合物[（18）F]3表现出Ki = 3.6 nM的D3亲和力，增加的亚型选择性（Ki（D2 /D3）= 60），以及对5-HT 1A和α1受体的低亲和力（Ki（5-HT 1A/D3）= 34; Ki（α1 /D3）= 100）。通过降低前体胺（57 mM）的必要浓度（其在碱性条件下与[（18）F]氟苯基偶氮羧酸叔丁酯反应）来优化类似物[（18）F]4的两步放射合成。碱（Cs2 CO 3，23 mM）的优化和反应温度的调节导致在35°C下5分钟后的放射化学产率为63%。将优化的反应条件转移到[（18）F]3的合成中，总合成时间为30-35 min后，总非衰变校正产率为8-12%，比活度为32-102 GBq/µmol。这为进一步的临床前研究提供了具有改进的选择性和放射合成属性的D3放射性配体候选物。
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.