Syntheses and evaluation of a homologous series of aza-vesamicol as improved radioiodine-labeled probes for sigma-1 receptor imaging
Syntheses and evaluation of a homologous series of aza-vesamicol as improved radioiodine-labeled probes for sigma-1 receptor imaging
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DOI：
10.1016/j.bmc.2019.03.054
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发表时间：
2019-05-15
影响因子：
3.5
通讯作者：
Odani, Akira
中科院分区：
文献类型：
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作者：
Ogawa, Kazuma;Masuda, Ryohei;Odani, Akira
用于确定Sigma-1受体表达水平的Sigma-1受体成像探针对于各种疾病的诊断和针对Sigma-1受体的治疗药物的伴随诊断是可取的。在这项研究中，我们的目标是开发对Sigma-1受体具有更高亲和力的探针。为此，我们合成并评价了一些化合物，即维沙米考衍生物，其中在哌嗪环和苯环之间引入了不同链长的烷基。维沙米考衍生物与Sigma-1受体的结合亲和力随苯环和哌嗪环之间烷基链长的增加而增加。2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol(5)的Sigma-1受体具有最高的结合亲和力(K-I=5.8nM)；因此，我们在5的苯环上引入了放射性碘。放射性碘标记的探针[I-125]2-(4-(3-(4-碘苯基)丙基)哌嗪-1-基)环己烷-1-醇([I-125]10)在表达Sigma-1受体的DU-145细胞体内外都有很高的蓄积。[I-125]10与过量的Sigma受体配体氟哌啶醇共注射后，体内和体外的肿瘤蓄积显著减少，表明Sigma受体介导的肿瘤摄取。这些结果为开发Sigma-1受体成像探针提供了有用的信息。
Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol (5) (K-i=5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5. The radioiodine labeled probe [I-125]2-(4-(3-(4-iodophenyl)propyl) piperazin-1-yl)cyclohexan-1-ol ([I-125] 10) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both in vitro and in vivo. Co-injection of [I-125] 10 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo, indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes.