Evaluation of [11C]Cimbi-36 as an Agonist PET Radioligand for Imaging of 5-HT2A Receptors
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Purpose
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.
| Condition | Intervention |
|---|---|
|
Healthy |
Drug: Citalopram and Pindolol Dietary Supplement: Acute tryptophan depletion |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Basic Science |
| Official Title: | Evaluation of [11C]Cimbi-36 as an Agonist PET Radioligand for Imaging of 5-HT2A Receptors |
- Cerebral Cimbi-36 receptor binding in terms of binding potential (BP) at (1) baseline (2)acute tryptophan depletion (3) acute SSRI and pindolol (4) placebo [ Time Frame: 2 hours ] [ Designated as safety issue: No ]Cerebral Cimbi-36 receptor binding is measured with PET scanning for 2 hours. 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 BP.
| Estimated Enrollment: | 30 |
| Study Start Date: | January 2013 |
| Estimated Study Completion Date: | July 2014 |
| Estimated Primary Completion Date: | December 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: 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. |
Drug: Citalopram and Pindolol
Citalopram: selective serotonin reuptake inhibitor Pindolol: non-selective beta blocker and 5-HT1A receptor antagonist Other Names:
|
|
Placebo Comparator: Placebo
Placebo for pindolol: sugar tablets that resembles pindolol Placebo for ATD: amino acid drink balanced formula (containing tryptophan) Placebo for Seropram: NaCl infusion |
|
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Experimental: Acute tryptophan depletion
Amino acid drink without tryptophan. Ingested 4-5 hours prior to PET scanning.
|
Dietary Supplement: Acute tryptophan depletion
Amino acid drink without tryptophan
|
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts 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.
Contacts and Locations| Denmark | |
| Neurobiology Research Unit, Rigshospitalet | Recruiting |
| Copenhagen, Denmark, 2100 | |
| Contact: Gitte M Knudsen, DMSc +45 35456712 gmk@nru.dk | |
More Information
Additional Information:
Publications:
| Responsible Party: | Gitte Moos Knudsen, Professor, DMSc, Rigshospitalet, Denmark |
| ClinicalTrials.gov Identifier: | NCT01778686 History of Changes |
| Other Study ID Numbers: | 2012-002056-16 |
| Study First Received: | January 11, 2013 |
| Last Updated: | January 25, 2013 |
| Health Authority: | Denmark: Danish Health and Medicines Authority |
Keywords provided by Rigshospitalet, Denmark:
|
Positron Emission Tomography Serotonin 5-HT2A Radioligand |
Additional relevant MeSH terms:
|
Citalopram Tryptophan Serotonin Uptake Inhibitors Dexetimide Pindolol Serotonin Antidepressive Agents, Second-Generation Antidepressive Agents Psychotropic Drugs Central Nervous System Agents Therapeutic Uses Pharmacologic Actions Neurotransmitter Uptake Inhibitors Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action |
Serotonin Agents Physiological Effects of Drugs Antiparkinson Agents Anti-Dyskinesia Agents Parasympatholytics Autonomic Agents Peripheral Nervous System Agents Muscarinic Antagonists Cholinergic Antagonists Cholinergic Agents Adrenergic beta-Antagonists Adrenergic Antagonists Adrenergic Agents Antihypertensive Agents Cardiovascular Agents |
ClinicalTrials.gov processed this record on May 22, 2013