Healthy
Conditions
Keywords
Positron Emission Tomography, Serotonin, 5-HT2A, Radioligand
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.
Interventions
DRUGCitalopram and Pindolol
Citalopram: selective serotonin reuptake inhibitor Pindolol: non-selective beta blocker and 5-HT1A receptor antagonist
OTHERPlacebo
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.
DIETARY_SUPPLEMENTAcute tryptophan depletion
Sponsors
Gitte Moos Knudsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
Yes
Inclusion criteria
* Age \> 18 years * Generally healthy
Exclusion criteria
* primary psychiatric disorder * current or previous neurological disease, severe somatic disease or taking medications that can influence the results. * non-fluent in danish or severe visual or hearing impairment * current or previous learning difficulties * pregnancy or lactating * contraindications for magnetic resonance scanning * alcohol or drug abuse * allergy to any of the used medications * participation in studies with radioactivity (\>10 mSv) within the last year or significant occupational exposure to radioactivity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Neocortical [11C]Cimbi-36 BPND From Baseline to Intervention in Each Arm | 2 hours | Cerebral Cimbi-36 receptor binding is measured with PET scanning for 2 hours, at baseline and after intervention. The resultant time-activity curves for brain tissue are used together with time-activity curves obtained with blood samples and kinetic modelling to yield unitless values of BPND at baseline and after intervention, respectively. As outcome, the mean percent difference from baseline to intervention in each arm is measured. |
Countries
Denmark
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Citalopram and Pindolol 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.
Citalopram and Pindolol: Citalopram: selective serotonin reuptake inhibitor
Pindolol: non-selective beta blocker and 5-HT1A receptor antagonist | 8 |
| Placebo Placebo for pindolol: sugar tablets that resembles pindolol
Placebo for ATD: amino acid drink balanced formula (containing tryptophan)
Placebo for Seropram: NaCl infusion
Placebo: 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. | 8 |
| Acute Tryptophan Depletion Amino acid drink without tryptophan. Ingested 4-5 hours prior to PET scanning.
Acute tryptophan depletion | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Acute Tryptophan Depletion | Citalopram and Pindolol | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 8 Participants | 8 Participants | 24 Participants |
| Age, Continuous | 22.6 years STANDARD_DEVIATION 2.5 | 22.9 years STANDARD_DEVIATION 3.2 | 22.4 years STANDARD_DEVIATION 2.1 | 22.6 years STANDARD_DEVIATION 2.6 |
| Region of Enrollment Denmark | 8 participants | 8 participants | 8 participants | 24 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 1 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Percent Change in Neocortical [11C]Cimbi-36 BPND From Baseline to Intervention in Each Arm
Cerebral Cimbi-36 receptor binding is measured with PET scanning for 2 hours, at baseline and after intervention. The resultant time-activity curves for brain tissue are used together with time-activity curves obtained with blood samples and kinetic modelling to yield unitless values of BPND at baseline and after intervention, respectively. As outcome, the mean percent difference from baseline to intervention in each arm is measured.
Time frame: 2 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Citalopram and Pindolol | Percent Change in Neocortical [11C]Cimbi-36 BPND From Baseline to Intervention in Each Arm | 7.4 percent change | Standard Deviation 16 |
| Placebo | Percent Change in Neocortical [11C]Cimbi-36 BPND From Baseline to Intervention in Each Arm | 0.6 percent change | Standard Deviation 7.2 |
| Acute Tryptophan Depletion | Percent Change in Neocortical [11C]Cimbi-36 BPND From Baseline to Intervention in Each Arm | 3.8 percent change | Standard Deviation 0.2 |