Neurobiology Research Unit , Rigshospitalet, Blegdamsvej 9 , 2100 Copenhagen , Denmark.
Department for Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , 2100 Copenhagen , Denmark.
ACS Chem Neurosci. 2019 Sep 18;10(9):3961-3968. doi: 10.1021/acschemneuro.9b00132. Epub 2019 Apr 22.
The latest addition to the serotonin (5-HT) receptor family is the 5-HT receptor (5-HTR). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HTR available. But, the (arylpiperazinyl-butyl)oxindole scaffold provides a promising lead structure for this purpose. Here, we synthesized 12 (arylpiperazinyl-butyl)oxindole derivatives and in vitro affinity screening identified two structures with suitable affinity and selectivity to be radiolabeled and tested as 5-HTR selective PET tracers. Next, the radiolabeled products [F]ENL09 and [F]ENL10 were evaluated as PET tracers in rats. Both tracers were found to be P-gp substrates, but after P-gp inhibition the brain uptake showed a regional distribution in line with the known 5-HTR distribution. The [F]ENL10 brain binding was displaceable with a 5-HTR selective ligand, whereas [F]ENL09 was not. We find that [F]ENL10 is a promising 5-HTR selective PET tracer candidate that should be investigated in higher species.
血清素（5-HT）受体家族的最新成员是 5-HT 受体（5-HTR）。由于其与抑郁症或精神分裂症等各种疾病有关，该受体已成为药物靶点的研究热点。目前，尚无临床验证的 5-HTR 正电子发射断层扫描（PET）示踪剂可用。但是，（芳基哌嗪基-丁基）吲哚酮支架为此提供了有希望的先导结构。在这里，我们合成了 12 种（芳基哌嗪基-丁基）吲哚酮衍生物，并通过体外亲和筛选鉴定了两种具有合适亲和力和选择性的结构，可被放射性标记并用作 5-HTR 选择性 PET 示踪剂进行测试。接下来，放射性标记产物 [F]ENL09 和 [F]ENL10 被评估为大鼠中的 PET 示踪剂。两种示踪剂均被发现是 P-糖蛋白（P-gp）的底物，但在 P-gp 抑制后，脑摄取显示出与已知 5-HTR 分布一致的区域分布。[F]ENL10 的脑结合可被 5-HTR 选择性配体置换，而 [F]ENL09 则不能。我们发现 [F]ENL10 是一种很有前途的 5-HTR 选择性 PET 示踪剂候选物，应在更高种属中进行研究。
