Conditions: Healthy
Keywords: Positron Emission Tomography Serotonin 5-HT2A Radioligand
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The purpose of this project was to introduce the recently developed positron emission tomography (PET) tracer \[11C\]Cimbi-36 for use in clinical studies and to investigate the ability of the tracer to quantify the 5-HT2A receptor in the human brain. As a receptor agonist, \[11C\]Cimbi-36 binding will provide a more functional picture of 5-HT2A receptors, while this binding is thought to be correlated to brain serotonin levels. Both measurement of signaling through the 5-HT2A receptor and measurement of serotonin levels in vivo would have great scientific relevance for significant diseases such as depression and schizophrenia.

Detailed description:
The serotonin 2A (5-HT2A) receptor is the most abundant excitatory serotonin (5-HT, 5-hydroxytryptamine) receptor in the human brain, and multiple positron emission tomography (PET) studies have investigated the 5-HT2A receptors in the human brain using antagonist radioligands. However, the currently available antagonist PET radioligands bind the total pool of 5-HT2A receptor receptors whereas a 5-HT2A receptor agonist binds the high-affinity subgroup of the receptors which are also G-protein coupled, and thus hypothesized to be the functional relevant population of receptors. At the Center for Integrated Molecular Brain Imaging (CIMBI), a novel agonist PET radioligands for brain imaging of 5-HT2A receptors was recently validated in animals (Ettrup et al. 2011, EJNMMI). In the human brain, \[11C\]Cimbi-36 was validated as a selective 5-HT2A receptor agonist PET radioligand through a blocking study with the 5-HT2A receptor antagonist pharmaceutical ketanserin. In this validation study, the biodistribution and kinetic modelling of \[11C\]Cimbi-36 binding in the human brain was also validated. With these studies, investigators will test the most promising of these, \[11C\]Cimbi-36, in clinical trials, where it will provide a novel method for detecting dysfunction in the 5-HT system. The specific aim of this clinical trial is:

\- To examine the effect of acute alterations in 5-HT levels on cerebral \[11C\]Cimbi-36 binding in healthy volunteers who will be PET-scanned at baseline and after pharmacological or dietary interventions that either increase or decrease cerebral 5-HT levels.

It is hypothesized that this novel agonist radioligand will provide both a more physiological relevant measure of the 5-HT2A receptors and also reflect levels of cerebral 5-HT in humans, more specifically:

BP will decrease after pindolol and selective serotonin reuptake inhibitor (SSRI) treatment and increase after acute tryptophan depletion (ATD). Placebo will leave binding potential (BP) unchanged.

Arms:
arm 1: Citalopram intravenous infusion starting 30 min before scanning, 40 mg/h for 1 hour.

Pindolol peroral administration starting 3 days before scanning:

Day 1: 2.5 mg 3 times daily, day 2: 5 mg 3 times daily, day 3: 7.5 mg 3 times daily, Day 4 (scan day) 7.5 mg morning and noon. arm 2: Placebo for pindolol: sugar tablets that resembles pindolol

Placebo for ATD: amino acid drink balanced formula (containing tryptophan)

Placebo for Seropram: NaCl infusion arm 3: Amino acid drink without tryptophan. Ingested 4-5 hours prior to PET scanning.

Interventions: intervention 1: Citalopram and Pindolol intervention 2: Placebo intervention 3: Acute tryptophan depletion
Intervention descriptions: intervention 1: Citalopram: selective serotonin reuptake inhibitor

Pindolol: non-selective beta blocker and 5-HT1A receptor antagonist intervention 2: On the second PET scanning day, subjects received a protein drink as well as a 50 ml saline infusion over 1 hour starting 30 min before PET scanning. intervention 3: None

Protocol document: