Neurochemical characterization of 5-HT2AR partial agonists with simultaneous PET-MRI.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism – May 01, 2025
Source: PubMed
Summary
Groundbreaking imaging techniques reveal how different psychedelic compounds interact with brain chemistry. Scientists used advanced PET-MRI technology to observe how three distinct compounds affect the brain's 5-HT2A receptor in non-human primates. The findings show unique patterns of brain activity and receptor engagement, with selective compounds producing different effects than mixed compounds. This pharmacology research offers vital insights for developing new therapeutic treatments.
Abstract
Understanding neuromodulatory effects of serotonin 2A receptor (5-HT2AR) 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-HT2AR 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 [11C]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-HT2AR 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.