DSP-2342, a novel 5-hydroxytryptamine 2A/7 receptor antagonist, has therapeutic potential for behavioral and psychological symptoms of dementia

In an aging society, behavioral and psychological symptoms of dementia (BPSD) have emerged as a major public health concern. BPSD includes diverse symptoms such as psychosis, anxiety, and agitation/aggression. Although antipsychotics are widely used to manage BPSD, their use is limited because of safety concerns, particularly extrapyramidal symptoms associated with dopamine D 2 receptor antagonism. Therefore, there is a need for antipsychotic drugs that are effective without relying heavily on D 2 receptor blockade. Here, we report DSP-2342, a novel selective 5-hydroxytryptamine 2A/7 (5-HT 2A /5-HT 7 ) receptor antagonist, which exhibits very low affinity for D 2 receptors. A mouse-behavior phenotyping platform predicted that DSP-2342 possesses antipsychotic, anxiolytic, mood-stabilizing, and antidepressant signatures. Consistent with these predictions, DSP-2342 suppressed phencyclidine-induced hyperlocomotion in mice, reduced freezing in rat contextual fear conditioning test. DSP-2342 also attenuated aggressive behavior in resident-intruder test in Alzheimer disease model mice. Furthermore, DSP-2342 restored cognitive performance in another Alzheimer disease model mice, as assessed by the novel object recognition test. To explore the underlying mechanism, a rat microdialysis study showed that DSP-2342 increased extracellular levels of noradrenaline, dopamine, and glutamate in the medial prefrontal cortex. The whole-brain c-Fos mapping revealed that DSP-2342 activated multiple brain regions and demonstrated a synergistic integration of 5-HT 2A and 5-HT 7 receptor antagonism, potentially underlying its distinctive pharmacological profile. Collectively, these findings suggest that the broad pharmacological effects of DSP-2342 through dual antagonism of 5-HT 2A and 5-HT 7 receptors may enable the management of diverse BPSD while maintaining a favorable safety profile. Significance Statement DSP-2342, a novel 5-hydroxytryptamine 2A/7 antagonist, shows preclinical efficacy across behavioral and psychological symptoms of dementia (BPSD)—including psychosis, anxiety, and agitation—while improving cognition. Unlike typical antipsychotics, it has very low dopamine D2 affinity, suggesting lower motor side-effect risk and a safer profile for BPSD.