Multimodal Neuroimaging for the PK/PD Profile of NLX-204: A Biased 5-HT_1A Receptor Agonist.

IF 4.1 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Neuroscience Pub Date : 2025-06-30 DOI:10.1021/acschemneuro.5c00342

Violette Richin, Marco Valdebenito, Caroline Bouillot, Sandrine Bouvard, Sébastien Daligault, Benjamin Vidal, Adrian Newman-Tancredi, Wael Zeinyeh, Luc Zimmer

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引用次数: 0

Abstract

NLX-204, a highly selective biased agonist for serotonin 5-HT_1A receptors, demonstrates strong affinity and preferentially elicits ERK1/2 phosphorylation, a response linked to antidepressant activity. Preclinical studies in rodent models confirm its potential as an effective and rapid-acting treatment for depression. In the present study, we performed a pharmacokinetic and pharmacodynamic characterization of NLX-204 by means of neuroimaging techniques. Radiolabeling of NLX-204 with fluorine-18 was used to assess its brain distribution and labeling kinetics via PET microdosing imaging in rats. Its pharmacodynamics were further investigated through a dose-response study in awake, freely moving rats using functional ultrasound (fUS) imaging. This unique combination of PET and fUS brain imaging data demonstrates that NLX-204 specifically engages 5-HT_1A receptors in the rat brain, eliciting robust activation in specific cortical regions. These results support the potential of NLX-204 as a promising candidate for the treatment of mood disorders.

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NLX-204的多模态神经影像学：一种偏向的5-HT1A受体激动剂。

NLX-204是5-羟色胺5-HT1A受体的高度选择性偏倚激动剂，具有很强的亲和力，并优先引发ERK1/2磷酸化，这是一种与抗抑郁活性相关的反应。啮齿动物模型的临床前研究证实了其作为一种有效和快速治疗抑郁症的潜力。在本研究中，我们通过神经成像技术对NLX-204进行了药代动力学和药效学表征。用氟-18对NLX-204进行放射性标记，通过PET微给药成像研究其在大鼠脑内的分布和标记动力学。利用功能超声（fUS）成像技术对清醒、自由活动的大鼠进行剂量反应研究，进一步研究其药效学。这种独特的PET和fUS脑成像数据的结合表明，NLX-204特异性地与大鼠大脑中的5-HT1A受体结合，在特定的皮质区域引发强烈的激活。这些结果支持了NLX-204作为治疗情绪障碍的有希望的候选药物的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL

CiteScore

9.20

自引率

4.00%

发文量

323

审稿时长

1 months

期刊介绍： ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research