Neurochemical characterization of 5-HT 2A R partial agonists with simultaneous PET-MRI

Psilocybin, lisuride, and 25CN-NBOH, three serotonin 2A receptor agonists with different pharmacological profiles, produce distinct brain blood flow patterns in anesthetized nonhuman primates. Psilocybin and lisuride, which are mixed partial agonists, caused biphasic cerebral blood volume changes, while the selective agonist 25CN-NBOH produced monophasic increases. Cortical receptor occupancy for psilocybin plateaued at 60 µg/kg (32%), similar to that of a lower dose of lisuride (31%). 25CN-NBOH had lower occupancy (7%) but larger blood volume changes. The relationship between blood volume and receptor occupancy appeared linear for lisuride and 25CN-NBOH but not for psilocybin. These differences may stem from the mixed affinity profiles of the agonists, providing insights for developing psychiatric therapeutics.

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Abstract

Understanding neuromodulatory effects of serotonin 2A receptor (5-HT 2A R) agonists with diverse pharmacological profiles is relevant to advancing psychedelic-related drug applications. We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) to examine partial agonists with varying 5-HT 2A R affinities and selectivity profiles: psilocybin (30, 60, and 90 µg/kg), lisuride (5 µg/kg), and 25CN-NBOH (15 µg/kg). Receptor occupancy was assessed with [ 11 C]MDL-100907 PET, and cerebral blood volume (CBV) changes were measured with phMRI. Mixed partial agonists psilocybin and lisuride evoked biphasic CBV responses, whereas the selective 25CN-NBOH produced monophasic CBV increases. Cortical occupancy for psilocybin plateaued at 60 µg/kg (32%), whereas a lower dose of lisuride (5 µg/kg) resulted in similar occupancy (31%). Administration of 25CN-NBOH resulted in lower occupancy (7%) but larger changes in CBV compared to psilocybin and lisuride. The associations between CBV and 5-HT 2A R occupancy appear linear for lisuride and 25CN-NBOH, but not for psilocybin. We speculate that the temporal and spatial differences in hemodynamic responses of the three agonists could stem from mixed affinity profiles. This work provides an understanding of pharmacological impacts of mixed serotonergic agonists being pursued as therapeutics for psychiatric conditions, offering valuable insights for future drug applications and development strategies.