18F-labeled FAUC 346 and BP 897 derivatives as subtype-selective potential PET radioligands for the dopamine D3 receptor
18F-labeled FAUC 346 and BP 897 derivatives as subtype-selective potential PET radioligands for the dopamine D3 receptor
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DOI：
10.1002/cmdc.200700327
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发表时间：
2008-05-01
期刊：
影响因子：
3.4
通讯作者：
Gmeiner, Peter
中科院分区：
文献类型：
--
作者：
Hocke, Carsten;Prante, Olaf;Gmeiner, Peter
多巴胺D3受体的中性粒细胞传递障碍与几种神经精神疾病有关，特别是与药物成瘾有关。在此，我们报道了通过3D-QSAR分析对新的氟烷氧基取代受体配体的D3选择性进行计算机辅助预测。作为D3选择性先导化合物Fauc 346和BP 879的紧密类似物，合成并评价了(19)F取代的测试化合物4a-d。体外研究它们在中国仓鼠卵巢(CHO)细胞中的结合特性，发现多巴胺D3亚型的K(I)值在0.12到0.69 nM之间。苯并噻吩基取代的羧胺4a(K(I)=0.12 nm)的选择性分别是结构上相关的D2(Long)和D4亚型的733倍和283倍。有丝分裂试验显示了部分激动剂的行为。基于这些数据，我们合成了[(18)F]氟乙氧基取代的放射性配体[(18)F]4a-d。合成了N-[4[4-(2-hydroxyphenyl)piperazin-1-yl]butyl]-2-carboxamides 3a-d，并用2-[(18)F]氟乙基对甲苯磺酸盐进行了两步标记。对~(18)F标记条件的优化使放化产率在24%~65%之间。
Disturbances of neutrotransmission at the dopamine D3 receptor are related to several neuropsychiatric diseases and in particular to drug addiction. Herein, we report the computer-assisted prediction of D3 selectivities of new fluoroalkoxy-substituted receptor ligands by means of 3D-QSAR analysis. As close analogues of the D3-selective lead compound FAUC 346 and BP 879, the (19)F-substituted test compounds 4a-d were synthesized and evaluated. In vitro investigation of their binding characteristics in transfected Chinese Hamster Ovary (CHO) cells led to excellent K(i) values between 0.12 and 0.69 nM at the dopamine D3 subtype. The benzothiophene-substituted carboxamide 4a (K(i)=0.12nM) displayed 733 and 283-fold selectivity over the structurally related D2(Long) and D4 subtypes, respectively. Mitogenesis assays showed the behavior of partial agonists. Based on these data, we synthesized the [(18)F]fluoroethoxy-substituted radioligands [(18)F]4 a-d The N-[4[4-(2-hydroxyphenyl)piperazin-1-yl]butyl]-2-carboxamides 3 a-d were prepared and labeled with 2-[(18)F]fluoroethyltosylate in a two-step procedure. Optimization of the (18)F-labeling conditions led to radiochemical yields between 24 and 65 %.