Synthesis and in vivo evaluation of halogenated N,N-Dimethyl-2-(2′-amino-4′-hydroxymethylphenylthio)benzylamine derivatives as PET serotonin transporter ligands
Synthesis and in vivo evaluation of halogenated N,N-Dimethyl-2-(2′-amino-4′-hydroxymethylphenylthio)benzylamine derivatives as PET serotonin transporter ligands
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DOI：
10.1021/jm0707929
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发表时间：
2008-01-24
影响因子：
7.3
通讯作者：
Goodman, Mark M.
中科院分区：
文献类型：
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作者：
Jarkas, Nachwa;Voll, Ronald J.;Goodman, Mark M.
N，N-二甲基-2-（2 '-氨基-4'-羟甲基苯硫基）苄胺（38）在A环上被取代，据报道对人脑5-羟色胺转运蛋白（SERT）显示出高的结合亲和力和选择性。为了探索在苯硫基苯基核结构的环B上取代的化合物的潜力，合成了38的三种衍生物：N，N-二甲基-2-（2 '-氨基-4'-羟甲基-苯硫基）-5-氟苄胺（35），N，N-二甲基-2-（2 ′-氨基-4 ′-羟甲基-苯硫基）-5-溴苄胺（36）和N，N-二甲基-2-（2 ′-氨基-4 ′-羟甲基-苯硫基）-5-碘苄胺（37）。在转染人SERT、去甲肾上腺素转运蛋白（NET）和多巴胺转运蛋白（DAT）的细胞中进行的体外结合研究显示，35、36和37显示出高SERT亲和力，K（i）s（SERT）分别为1.26、0.29和0.31 nM（vs [H-3]西酞普兰）。[C-11-（35）、[C-11-（36）和[C-11-（37）通过其单甲基前体16、17和18与[C-11]碘甲烷的甲基化反应制备，放射化学产率分别为28、11和14%。[C-11-（35）]、[C-11-（36）]和[C-11-（37）]的microPET图像显示在富含SERT的猴脑区域中的高摄取，在注射后85 min时中脑与小脑的峰值比率分别为3.41、3.24和3.00。[C-11-（35）、[C-11-（36）和[C-11-（37）]的体内结合显示对SERT具有特异性，因为用西酞普兰（一种有效的SERT配体）置换可将SERT富集区域中的放射性降低至小脑水平。这些结果表明，[C-11-（35）、[C-11-（36）和[C-11-（37）]可能是通过PET和用碘-123放射性标记37来绘制人SERT的潜在试剂，这可以提供第一种表现出快速动力学的SPECT SERT成像剂。
N,N-Dimethyl-2-(2'-amino-4'-hydroxymethylphenylthio)benylamine (38), substituted on ring A, was reported to display high binding affinity and selectivity to the human brain serotonin transporter (SERT). In an attempt to explore the potential of compounds substituted on ring B of the phenylthiophenyl core structure, three derivatives of 38 were synthesized: N,N-dimethyl-2-(2'-amino-4'-hydroxymethyl-phenylthio)-5-fluorobenzylamine (35), N,N-dimethyl-2-(2'-amino-4'-hydroxymethyl-phenylthio)-5-bromobenzylamine (36), and N,N-dimethyl-2-(2'-amino-4'-hydroxymethyl-phenylthio)-5-iodobenzylamine (37). The in vitro binding studies in cells transfected with human SERT, norepinephrine transporter (NET), and dopamine transporter (DAT) showed that 35, 36, and 37 exhibited high SERT affinity with K(i)s (SERT) = 1.26, 0.29, and 0.31 nM (vs [H-3]citalopram), respectively. [C-11-(35), [C-11-(36), and [C-11-(37) were prepared by methylation of their monomethyl precursors 16, 17, and 18, with [C-11]iodomethane in 28, 11, and 14% radiochemical yields, respectively. The microPET images of [C-11-(35), [C-11-(36), and [C-11-(37) showed high uptake in the monkey brain regions rich in SERT with peak midbrain to cerebellum ratios of 3.41, 3.24, and 3.00 at 85 min post-injection, respectively. In vivo bindings of [C-11-(35), [C-11-(36), and [C-11-(37) were shown to be specific to the SERT as displacement with citalopram (a potent SERT ligand) reduced radioactivity in SERT-rich regions to the cerebellum level. These results suggest that [C-11-(35), [C-11-(36), and [C-11-(37) could be potential agents for mapping human SERT by PET and radiolabeling 37 with iodine-123, which could afford the first SPECT SERT imaging agent exhibiting fast kinetics.