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 D2 receptor antagonism. Therefore, there is a need for antipsychotic drugs that are effective without relying heavily on D2 receptor blockade. Here, we report DSP-2342, a novel selective 5-hydroxytryptamine 2A/7 (5-HT2A/5-HT7) receptor antagonist, which exhibits very low affinity for D2 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-HT2A and 5-HT7 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-HT2A and 5-HT7 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.