Evaluation of [11C]Cimbi-36 as an Agonist PET Radioligand for Imaging of 5-HT2A Receptors

Gitte Moos Knudsen

Status: Completed

Conditions: Healthy

Treatments: Other: Placebo; Drug: Citalopram and Pindolol; Dietary Supplement: Acute tryptophan depletion

Study type: Interventional

Funder types: Other

Identifiers

NCT01778686

2012-002056-16

Details and patient eligibility

About

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.

Full 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.

Enrollment: 24 patients

Sex: All

Ages: 18 to 100 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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24 participants in 3 patient groups, including a placebo group

Citalopram and Pindolol

Experimental group

Description:

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.

Treatment:

Drug: Citalopram and Pindolol

Placebo

Placebo Comparator group

Description:

Placebo for pindolol: sugar tablets that resembles pindolol Placebo for ATD: amino acid drink balanced formula (containing tryptophan) Placebo for Seropram: NaCl infusion

Treatment:

Other: Placebo

Acute tryptophan depletion

Experimental group

Description:

Amino acid drink without tryptophan. Ingested 4-5 hours prior to PET scanning.

Treatment:

Dietary Supplement: Acute tryptophan depletion