N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.

[(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT(2A) receptor agonist binding in the living human brain with PET.

[ 11 C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT 2A ) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with INTRODUCTIONThe neurotransmitter serotonin (5-HT) is a modulator of a vast variety of normal physiologic effects and is also involved in the pathophysiology of central nervous system disorders such as depression and schizophrenia. The serotonin 2A (5-HT 2A ) receptor is the main excitatory 5-HT receptor in the human central nervous system, it is responsible for the hallucinogenic effects of recreational agonist drugs such as lysergic acid diethylamide and psilocybin, and 5-HT 2A receptor antagonism is a characteristic of atypical antipsychotics. 1 Furthermore, changes in 5-HT 2A receptor levels have been linked to the pathophysiology of human diseases such as depression. 2,3 Positron emission tomography (PET) has unsurpassed sensitivity and selectivity to detect and quantify specific proteins and processes in the human brain. Positron emission tomography imaging with radioligands is a widely used tool to quantify differences in receptor binding, for example, between patient and control groups, to quantify receptor occupancy of pharmacological interventions or to measure neurotransmitter release in vivo. 4,5 In clinical studies, 5-HT 2A receptor antagonists have for decades been in use as PET radioligands, most notably [ 18 F]altanserin and [ 11 C]MDL100907. 6 However, agonist PET radioligands may functionally possess several advantages over antagonists. Importantly, agonist radioligands in the dopamine system have an increased sensitivity to endogenously released neurotransmitter. Here, several studies using pharmacologically increased dopamine