Changes in Striatal [11C]ORM-13070 Binding Elicited by Changing Levels of Endogenous Noradrenaline
Condition: Changes in Striatal [11C]ORM-13070 Binding.
Study type: Interventional
Phase: Phase 1

Summary: 
      The primary objective of the study is to further investigate whether striatal [11C]ORM-13070
      uptake can be reduced by physiological and pharmacological challenges that increase the
      synaptic concentrations of noradrenaline in the human brain. Each subject will undergo 3 PET
      scans, a baseline PET scan and two scans with noradrenaline challenges: intravenous
      administration of ketamine and oral administration of atomoxetine combined with a cold
      pressor test where the subject's foot is placed in an 8 °C water basin. Eight healthy male
      subjects will be included in the study.
    

Detailed description: 
      Objectives

      The primary objective of the study is to further investigate whether striatal [11C]ORM-13070
      uptake can be reduced by physiological and pharmacological challenges that increase the
      synaptic concentrations of the endogenous alpha2C-adrenoceptor agonist, noradrenaline, in the
      human brain.

      Methodology

      PET will be used to study the effects of two different noradrenaline challenges on the
      striatal uptake of the novel alpha2C-adrenoceptor imaging agent, [11C]ORM-13070. Each of the
      eight study subjects will undergo one baseline PET scan without any pretreatment and two
      scans with two different noradrenaline challenges: i.v. infusion of ketamine and a single
      oral dose of atomoxetine combined with cold pressor test. The sequence of the baseline scan
      and the other scans for each subject will be based on balanced randomization. Double-blind
      administration of the pretreatments will not be possible, but the PET scanning data will be
      analyzed by a person who is not aware of the treatment identity. Venous blood samples will be
      collected for determination of concentrations of the [11C]ORM-13070 tracer and its
      radioactive metabolites, the test drugs atomoxetine and ketamine, and endogenous
      noradrenaline as a biomarker of the employed challenges. Blood pressure and heart rate will
      be measured as physiological indicators of sympathetic activation. Subject safety will be
      monitored by vital signs, questioning and clinical observation. The binding potential of the
      tracer in the striatum at baseline will be compared with the tracer binding potential after
      each of the noradrenaline challenges.

      Sample size

      Eight healthy male subjects will be included in the study. Discontinued subjects may be
      replaced by new subjects as decided by the Principal Investigator

      Duration of treatment

      After the screening visit, there will be an interval of no more than 45 days before the first
      PET visit. Each subject will undergo 3 PET scans: a baseline PET scan, and two scans with
      noradrenaline challenges. The PET experiments of each subject will be separated by intervals
      of at least 5 days. An end-of-study visit will take place within 21 days after the last PET
      scan.

      Assessments

      Efficacy: Alpha2C-adrenoceptor occupancy in the caudate nucleus and putamen will be assessed
      using the PET imaging agent [11C]ORM-13070 after the administration of two noradrenaline
      challenges, ketamine and atomoxetine combined with the cold pressor test. Differences in
      striatal receptor occupancy of the tracer will be assessed using established reference tissue
      models and the binding potentials of the non-displaceable compartment (BPND) according to the
      equation: Occupancy = [(BPND bl - BPND challenge) / BPNDbl x 100%]. Plasma noradrenaline
      concentrations will be measured as a biochemical biomarker before and after the interventions
      to validate the employed noradrenaline challenges. Blood pressure and heart rate will be used
      as physiological biomarkers.

      Safety: Vital signs, subjective symptoms and ECG will be monitored during the PET visits.
      Subjects will remain at the study center for a minimum of 4 h after each PET scan, after
      which the subject will be discharged based on clinical evaluation with a safety check list.

      Pharmacokinetics: Venous blood samples will be collected for determination of concentrations
      of the [11C]ORM-13070 tracer and its radioactive metabolites, and the pretreatment agents
      atomoxetine and ketamine at pre-defined time points in order to provide information on the
      fraction of intact tracer in blood and to document the exposure to the pharmacological agents
      during the PET scans. No formal pharmacokinetic calculations will be performed.

      Statistical methods:

      Efficacy, safety and pharmacokinetics: Differences in striatal [11C]ORM-13070 uptake between
      the baseline condition and the different pretreatments will be considered a primary outcome
      variable and statistical analysis will be carried out with analysis of variance. Descriptive
      statistical analysis of the tracer fractions in blood during the scans and the concentrations
      of the employed pretreatment agents will be carried out. Demographic and other baseline data,
      laboratory safety determinations, physical examination, BP, HR, ECG, AEs and concomitant
      treatments will be summarised with descriptive statistics or listed.
    

Intervention name(s): Ketamine; Atomoxetine; Cold pressor test; Placebo
Intervention type(s): Drug; Drug; Other; Drug
Other intervention name(s): Ketalar; Strattera; Cold stimulation of the subject's foot
Intervention MeSH terms: Ketamine; Atomoxetine Hydrochloride
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: PET; striatum; receptor occupancy; noradrenaline; alpha2c