Multimodal Neuroimaging for the PK/PD Profile of NLX-204: A Biased 5-HT1A Receptor Agonist

NLX-204, a highly selective biased agonist for serotonin 5-HT1A 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-HT1A 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.