Serotonin 2A Receptor Agonist Binding in the Human Brain with [11C]Cimbi-36

A new radioactive tracer, [11C]Cimbi-36, was tested in 29 healthy volunteers for brain imaging using PET scans. This tracer binds to serotonin 2A receptors, which are involved in mood and perception, and is an agonist, meaning it activates the receptor rather than blocking it. High uptake in the brain matched known locations of these receptors. A two-tissue compartment model using arterial blood samples gave the most accurate measurements. In five subjects given a blocker drug (ketanserin), tracer binding decreased in cortical areas but not in the cerebellum, confirming the tracer's specificity and that the cerebellum can serve as a reference region. This is the first agonist PET radioligand to successfully image these receptors in humans.

Study at a glance

Abstract

[ 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 [ 11 C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT 2A receptors with [ 11 C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [ 11 C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [ 11 C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT 2A receptor antagonist ketanserin before a second PET scan significantly decreased [ 11 C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [ 11 C]Cimbi-36 binding is selective for 5-HT 2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT 2A receptors in the human brain. Thus, we here describe [ 11 C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT 2A receptors in the human brain.