Competition With Striatal [11C]ORM-13070 Binding by Atipamezole and Endogenous Noradrenaline

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to validate [11C]ORM-13070 as an alpha2C-adrenoceptor imaging agent for human positron emission tomography (PET) studies of brain alpha2C-adrenoceptor occupancy.

Official Title
-----------------
Competition With Striatal [11C]ORM-13070 Binding by Atipamezole and Endogenous Noradrenaline - a PET Study in Healthy Human Subjects

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

Intervention / Treatment
-----------------
* Drug: Atipamezole
* Drug: Atomoxetine
* Drug: Ketamine
* Other: Cold pressor test
* Drug: Insulin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent (IC) obtained. Good general health ascertained by detailed medical history, laboratory investigations and physical examination. Males between 20 and 40 years of age (inclusive). Body mass index (BMI) between 18-28 kg/m2 inclusive (BMI = weight/height2). Weight 60-100 kg (inclusive). Exclusion Criteria: Suspected poor compliance with the protocol or inability to communicate well with the study personnel. Veins unsuitable for repeated venipuncture. CYP2D6 slow metabolizer or ultrarapid metabolizer genotype. Evidence of clinically significant cardiovascular, renal, hepatic, haematological, gastrointestinal, pulmonary, metabolic-endocrine, neurological, urogenital or psychiatric disease as judged by the investigator. Any condition requiring regular concomitant medication including herbal products or likely to need any concomitant medication during the study. Susceptibility to severe allergic reactions. Intake of any medication that could affect the outcome of the study, within 2 weeks prior to the tracer administration (2 months for enzyme inducing drugs like rifampicin or carbamazepine), or less than 5 times the half-life of the medication. Regular consumption of more than 21 units of alcohol per week (1 unit = 4 cl spirits, about 13 g of alcohol). Current use of nicotine-containing products more than 5 cigarettes or equivalent/day. Inability to refrain from using nicotine-containing products during the stay at the study centre. Inability to refrain from consuming caffeine-containing beverages during the stay at the study centre, e.g. propensity for headache when refraining from caffeine-containing beverages. Blood donation or loss of significant amount of blood within 2 months prior to the screening visit. Abnormal 12-lead electrocardiogram (ECG) finding of clinical relevance after 10 minutes rest in supine position at the screening visit, for example: QTc (calculated using Bazett's formula) > 450 msec, PR < 120 msec or > 210 msec, QRS < 70 msec or > 120 msec. Heart rate (HR) < 40 beats/minute or > 90 beats/minute after 10 minutes rest in supine position at the screening visit. At the screening visit, systolic blood pressure (BP) < 90 mmHg or > 140 mmHg after 10 minutes in supine position, diastolic BP < 50 mmHg or > 90 mmHg after 10 minutes in supine position. Any abnormal laboratory value, vital sign or physical examination result, which may in the opinion of the investigator interfere with the interpretation of the test results or cause a health risk to the subject if he takes part in the study. History of drug abuse or positive result in drug abuse test. Positive serology to human immunodeficiency virus antibodies (HIVAb), hepatitis B surface antigen (HBsAg) or hepatitis C virus antibodies (HCVAb). Anatomical abnormality in brain MRI which may in the opinion of the investigator interfere with the interpretation of the PET results. Any other condition that in the opinion of the investigator would interfere with the evaluation of the results or constitute a health risk to the subject. Participation in another clinical drug study within 3 months prior to this study. Participation in a prior PET study or other medical or occupational exposure to significant doses of ionizing radiation. Any contraindication to MRI of the brain.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Male

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

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

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atipamezole<br> | Drug: Atipamezole<br>* Administration of a single dose of 5-150 micrograms of atipamezole as an intravenous infusion<br>* Other names: ANTISEDAN VET;|
| Experimental: Atomoxetine<br> | Drug: Atomoxetine<br>* A single dose of 1.2 mg/kg of atomoxetine administered orally<br>* Other names: Strattera;|
| Experimental: Ketamine<br> | Drug: Ketamine<br>* A single dose of ketamine (approximately 60 mg) administered as an intravenous infusion<br>* Other names: Ketalar;|
| Experimental: Insulin-induced hypoglycemia<br> | Drug: Insulin<br>* Insulin administered as an intravenous infusion to induce hypoglycemia<br>* Other names: Insulin Actrapid;|
| Experimental: Cold pressor test<br> | Other: Cold pressor test<br>* 30-45 min cold pressor test of the foot<br>|
| Experimental: Placebo<br> | Drug: Placebo<br>* A single dose of placebo (capsules) administered orally<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Receptor occupancy | PET tracer (interventional drug) uptake in the brain is measured for 30 minutes by PET after various pharmacological and physiological pre-treatments. | 30 minutes | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
alpha2-adrenoceptor, receptor occupancy, positron emission tomography, [11C]ORM-13070, striatum, brain, noradrenaline, norepinephrine, endogenous, binding, Validation studies