Clinical trial NCT01778686: Evaluation of [11C]Cimbi-36 as an Agonist PET Radioligand for Imaging of 5-HT2A Receptors
Official title: Evaluation of [11C]Cimbi-36 as an Agonist PET Radioligand for Imaging of 5-HT2A Receptors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Healthy
Keywords: Positron Emission Tomography
Serotonin
5-HT2A
Radioligand
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2013-01-29
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: Percent Change in Neocortical [11C]Cimbi-36 BPND From Baseline to Intervention in Each Arm
timeFrame: 2 hours
Secondary outcomes:
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Neurobiology Research Unit, Rigshospitalet
Study officials:
affiliation: Neurobiology Research Unit, Rigshospitalet
name: Gitte M Knudsen, DMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.