Localization of serotonin 5‐HT2 receptors in living human brain by positron emission tomography using N1‐([11C]‐methyl)‐2‐BR‐LSD

A new radioligand, [11C]-MBL, selectively binds to serotonin 5-HT2 receptors in the brain, as shown by in vitro assays (Ki = 0.5 nM) and PET imaging in baboons and seven healthy human volunteers. In humans, highest binding occurred in frontal, temporal, and parietal cortex, with lower levels in caudate and putamen. Blocking with ketanserin confirmed specificity. Frontal cortex-to-cerebellum ratios ranged from 1.7 to 2.7, with older volunteers showing lower ratios, suggesting age-related decline in 5-HT2 receptor density. [11C]-MBL enables in vivo monitoring of these receptors in most human brain regions.

Study at a glance

Abstract

Abstract N1‐([ 11 C]‐Methyl)‐2‐Br‐LSD ([ 11 C]‐MBL) has been developed as a positron emission tomography (PET) imaging agent for serotonin 5‐HT 2 receptors. In vitro receptor binding assays with nonradioactive MBL show high‐affinity binding to serotonin 5‐HT 2 receptors (K i = 0.5 nM), a secondary interaction of 8‐fold lower affinity with dopamine D 2 receptors, and low‐affinity interactions with α 1 ‐adrenergic as well as serotonin 5‐HT 1 receptors. Intravenous injection of [ 11 C]‐MBL in a baboon led to selective labeling of cortical regions that was markedly blocked by prior administration of ketanserin, a selective 5‐HT 2 receptor antagonist. Clinical trials with [ 11 C]‐MBL have been conducted in seven normal human volunteers, and the regional distribution of radioactivity in the brain was distinctly serotonergic. Labeling was highest in frontal, temporal, and parietal cortex with lower levels observed in caudate and putamen. The tracer rapidly washed from the cerebellum and the low levels of activity in this brain region were used to define nonspecific binding. The maximum specificity was reached between 30 and 60 minutes postinjection when frontal cortex to cerebellum ratios ranged from 1.7 for a 52‐year‐old male to 2.7 for a 30‐year‐old male. In agreement with previous studies, a trend towards lower ratios (lower serotonin 5‐HT 2 receptor levels) was observed in older volunteers. These studies indicate that [ 11 C]‐MBL is a selective radioligand that can be used to monitor serotonin 5‐HT 2 receptor densities in vivo in most regions of the human brain.