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

NCT ID: NCT01778686

Last Updated: 2025-02-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2013-11-30

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.

Conditions

Healthy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Citalopram and Pindolol

Intervention Type: DRUG

Citalopram: selective serotonin reuptake inhibitor

Pindolol: non-selective beta blocker and 5-HT1A receptor antagonist

Placebo

Placebo for pindolol: sugar tablets that resembles pindolol

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

Placebo for Seropram: NaCl infusion

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

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.

Acute tryptophan depletion

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

Group Type: EXPERIMENTAL

Acute tryptophan depletion

Intervention Type: DIETARY_SUPPLEMENT

Interventions

Citalopram and Pindolol

Citalopram: selective serotonin reuptake inhibitor

Pindolol: non-selective beta blocker and 5-HT1A receptor antagonist

Intervention Type: DRUG

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.

Intervention Type: OTHER

Acute tryptophan depletion

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

Seropram; Hexapindol®; Amino acid drink without tryptophan

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Gitte Moos Knudsen

OTHER

Sponsor Role: lead

Responsible Party

Gitte Moos Knudsen

Professor, DMSc

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Gitte M Knudsen, DMSc

Role: PRINCIPAL_INVESTIGATOR

Neurobiology Research Unit, Rigshospitalet

Locations

Neurobiology Research Unit, Rigshospitalet

Copenhagen, , Denmark

Countries

Denmark

References

Ettrup A, Hansen M, Santini MA, Paine J, Gillings N, Palner M, Lehel S, Herth MM, Madsen J, Kristensen J, Begtrup M, Knudsen GM. Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers. Eur J Nucl Med Mol Imaging. 2011 Apr;38(4):681-93. doi: 10.1007/s00259-010-1686-8. Epub 2010 Dec 21.

Reference Type: BACKGROUND

PMID: 21174090 (View on PubMed)

Other Identifiers

2012-002056-16

Identifier Type: -

Identifier Source: org_study_id