Richin Violette, Valdebenito Marco, Bouillot Caroline, Bouvard Sandrine, Daligault Sébastien, Vidal Benjamin, Newman-Tancredi Adrian, Zeinyeh Wael, Zimmer Luc
Lyon Neuroscience Research Center, Université Claude Bernard Lyon 1, Inserm, CNRS, 69500 Bron, France.
Neurolixis, 81100 Castres, France.
ACS Chem Neurosci. 2025 Jul 16;16(14):2738-2746. doi: 10.1021/acschemneuro.5c00342. Epub 2025 Jun 30.
NLX-204, a highly selective biased agonist for serotonin 5-HT 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 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.
NLX-204是一种对血清素5-HT受体具有高度选择性的偏向性激动剂，具有很强的亲和力，并优先引发与抗抑郁活性相关的ERK1/2磷酸化反应。在啮齿动物模型中的临床前研究证实了其作为抑郁症有效且速效治疗方法的潜力。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特征分析。用氟-18对NLX-204进行放射性标记，通过大鼠正电子发射断层扫描（PET）微量给药成像来评估其脑部分布和标记动力学。通过在清醒、自由活动的大鼠中使用功能超声（fUS）成像进行剂量反应研究，进一步研究了其药效学。PET和fUS脑成像数据的这种独特组合表明，NLX-204特异性地作用于大鼠脑中的5-HT受体，在特定皮质区域引发强烈激活。这些结果支持了NLX-204作为治疗情绪障碍有前景候选药物的潜力。
