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

N1‐([¹¹C]‐Methyl)‐2‐Br‐LSD ([¹¹C]‐MBL) has been developed as a positron emission tomography (PET) imaging agent for serotonin 5‐HT₂ receptors. In vitro receptor binding assays with nonradioactive MBL show high‐affinity binding to serotonin 5‐HT₂ receptors (K_i = 0.5 nM), a secondary interaction of 8‐fold lower affinity with dopamine D₂ receptors, and low‐affinity interactions with α₁‐adrenergic as well as serotonin 5‐HT₁ receptors. Intravenous injection of [¹¹C]‐MBL in a baboon led to selective labeling of cortical regions that was markedly blocked by prior administration of ketanserin, a selective 5‐HT₂ receptor antagonist. Clinical trials with [¹¹C]‐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‐HT₂ receptor levels) was observed in older volunteers. These studies indicate that [¹¹C]‐MBL is a selective radioligand that can be used to monitor serotonin 5‐HT₂ receptor densities in vivo in most regions of the human brain.