This mini-review presents our current understanding of serotonin type 7 receptor research focusing on the possible network mechanisms underlying the behavioral action of receptor antagonists. The serotonin type 7 receptor is expressed widely throughout the nervous system and known to be involved in various cognitive and physiological mechanisms. It became a clinically significant target after the discovery that its selective antagonist SB 269970 can exert rapid-onset antidepressant effects either alone or in combination with lower doses of conventional antidepressant drugs. Further research has shown that administration of SB 269970 can effectively counteract negative neurobiological outcomes in various chronic stress paradigms. The authors hope they can introduce a wider scientific audience to this promising pharmacological target which, if successful, could in time lead to more discoveries and a better understanding of the underlying serotonin receptor biology as well as its clinical potential. HIGHLIGHTS.

01 Dec 2021·Journal of NeuroinflammationQ1 · MEDICINE

Autophagy protein NRBF2 attenuates endoplasmic reticulum stress-associated neuroinflammation and oxidative stress via promoting autophagosome maturation by interacting with Rab7 after SAH

Q1 · MEDICINE

ArticleOA

Author: Yan, Feng ; Cai, Jing ; Fu, Xiongjie ; Zhuang, Jianfeng ; Zeng, Hanhai ; Zhou, Hang ; Xu, Chaoran ; Li, Min ; Cao, Shenglong ; Chen, Huaijun ; Chen, Gao ; Peng, Yucong ; Yu, Qian

AbstractBackgroundNeuroinflammation and oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study is the first to show that activation of autophagy protein nuclear receptor binding factor 2 (NRBF2) could reduce endoplasmic reticulum stress (ERS)-associated inflammation and oxidative stress after SAH.MethodsMale C57BL/6J mice were subjected to endovascular perforation to establish a model of SAH. NRBF2 overexpression adeno-associated virus (AAV), NRBF2 small interfering RNAs (siRNA), lysosomal inhibitor-chloroquine (CQ), and late endosome GTPase Rab7 receptor antagonist-CID1067700 (CID) were used to investigate the role of NRBF2 in EBI after SAH. Neurological tests, brain water content, western blotting and immunofluorescence staining were evaluated.ResultsOur study found that the level of NRBF2 was increased after SAH and peaked at 24 h after SAH. In addition, we found that the overexpression of NRBF2 significantly improved neurobehavioral scores and reduced ERS, oxidative stress, and neuroinflammation in SAH, whereas the inhibition of NRBF2 exacerbated these phenotypes. In terms of mechanism, NRBF2 overexpression significantly promoted autophagosome maturation, with the downregulation of CHOP, Romo-1, TXNIP, NLRP3, TNF-α, and IL-1β expression through interaction with Rab7. The protective effect of NRBF2 on ERS-associated neuroinflammation and oxidative stress after SAH was eliminated by treatment with CQ. Meanwhile, it was also reversed by intraperitoneal injection of CID. Moreover, the MIT domain of NRBF2 was identified as a critical binding site that interacts with Rab7 and thereby promotes autophagosome maturation.ConclusionOur data provide evidence that the autophagy protein NRBF2 has a protective effect on endoplasmic reticulum stress-associated neuroinflammation and oxidative stress by promoting autophagosome maturation through interactions with Rab7 after SAH.

07 Jun 2021·Molecular PharmaceuticsQ2 · MEDICINE

Synthesis and Biological Evaluation of ^99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging

Q2 · MEDICINE

Article

Author: Molavipordanjani, Sajjad ; Emami, Saeed ; Amiri, Fereshteh Talebpour ; Abedi, Seyed Mohammad ; Hosseinimehr, Seyed Jalal ; Saednia, Shahnaz

With a poor prognosis, glioblastoma multiforme is the most aggressive tumor of the central nervous system in humans. The aim of this study was to develop novel tracers for the tumor targeting and imaging of overexpressed serotonin-7 receptors (5-HT₇Rs) in U-87 MG glioma xenografted nude mice. Two phenylpiperazine derivatives named as PHH and MPHH were designed, and the corresponding radiotracers ^99mTc-PHH and ^99mTc-MPHH were synthesized in high radiochemical purity (>95%). ^99mTc-MPHH showed a higher affinity to 5-HT₇Rs on U-87 MG cells compared to ^99mTc-PHH. In biodistribution studies, the radiocomplexes showed good brain uptake at 15 min combined with good radioactivity retention in the brain for 240 min. Regional rabbit brain studies indicated a higher radioactivity concentration in the hippocampus and diencephalon than in the cerebellum. Compared to ^99mTc-MPHH, the ^99mTc-PHH exhibited a significantly increased tumor uptake at 15 and 60 min, but the rapid blood clearance of ^99mTc-MPHH led to enhanced tumor-to-muscle ratios at 240 min. A significant reduction in tumor uptake 60 min after an injection of pimozide (5-HT₇ receptor antagonist) confirms the tumor uptake was receptor-mediated specifically. The tumor-to-contralateral muscle tissue ratio of ^99mTc-PHH and ^99mTc-MPHH in nude mice with U-87 MG xenograft was measured (5.25 and 4.65) at 60 min as well as (6.25 and 6.76) at 240 min, respectively.

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Indication	Highest Phase	Country/Location	Organization	Date
Psychotic Disorders	Preclinical	CA	NPS Pharmaceuticals, Inc.	-

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