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

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Citalopram and Pindolol
* Other: Placebo
* Dietary Supplement: Acute tryptophan depletion


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Citalopram and Pindolol<br>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<br>* Citalopram: selective serotonin reuptake inhibitor Pindolol: non-selective beta blocker and 5-HT1A receptor antagonist<br>* Other names: Hexapindol®;|
| Placebo Comparator: Placebo<br>Placebo for pindolol: sugar tablets that resembles pindolol Placebo for ATD: amino acid drink balanced formula (containing tryptophan) Placebo for Seropram: NaCl infusion | Other: Placebo<br>* 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.<br>|
| Experimental: Acute tryptophan depletion<br>Amino acid drink without tryptophan. Ingested 4-5 hours prior to PET scanning. | Dietary Supplement: Acute tryptophan depletion<br> <br> * Other names: Amino acid drink without tryptophan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 2 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Positron Emission Tomography, Serotonin, 5-HT2A, Radioligand