P4‐375: A Clinical Positron Emission Tomography (Pet) Study Investigating Occupancy at the 5‐ht6 Receptor After Multiple Oral Doses of Lu Ae58054 to Healthy Men

Schmidt, Ellen; Kuwabara, Hiroto; Areberg, Johan; Zaidi, Eram; Chamroonat, Wichana; Mathur, Anil; Wong, Dean F.

doi:10.1016/j.jalz.2014.07.144

Cited by 5 publications

(1 citation statement)

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“…The results of an in vivo positron emission tomography receptor occupancy study conducted among healthy participants taking idalopirdine, which became available after completion of the phase 2 study, were used to guide dose and schedule selection in the phase 3 studies, as suggested by the US Food and Drug Administration . A high 5-HT 6 receptor occupancy (>80%) was achieved at doses of 30 and 60 mg/d of idalopirdine, which was maintained for 24 hours, supporting the use of once daily dosing . Although there is an approximate 40% decrease in 5-HT 6 receptor expression among patients with Alzheimer disease compared with healthy individuals, there are also potential limitations in translating occupancy data from healthy individuals to those with a diseased brain …”

Section: Discussionmentioning

confidence: 99%

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease

Atri

Frölich

Ballard

et al. 2018

JAMA

131

111

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Section: Discussionmentioning

confidence: 99%

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease

Atri

Frölich

Ballard

et al. 2018

JAMA

131

111

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Serotonin 5-HT6 Receptor Antagonists in Alzheimer’s Disease: Therapeutic Rationale and Current Development Status

et al. 2016

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Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT receptor has received increasing attention, and a growing number of studies supported 5-HT receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT receptor antagonists. Subsequently, the number of patents protecting 5-HT chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.

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The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

Khoury

Grysman

Gold

et al. 2018

Expert Opinion on Investigational Drugs

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Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile. Areas covered: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I-III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD. Expert opinion: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.

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P4‐375: A Clinical Positron Emission Tomography (Pet) Study Investigating Occupancy at the 5‐ht6 Receptor After Multiple Oral Doses of Lu Ae58054 to Healthy Men

Cited by 5 publications

References 0 publications

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease

Serotonin 5-HT6 Receptor Antagonists in Alzheimer’s Disease: Therapeutic Rationale and Current Development Status

The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

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