I2PETHV - Imidazoline2 Binding Site in Healthy Volunteers
Condition: Healthy Volunteers; Alzheimer Disease; Molecular Imaging
MeSH terms: Alzheimer Disease
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The imdazoline2 binding site (I2BS) is known to reside inside astrocytes. Changes in the
      numbers of I2BS in post mortem tissue has implicated them in a range of psychiatric
      conditions such as depression and addiction, along with neurodegenerative disorders such as
      Alzheimer's disease and Huntington's chorea. Preclinical studies have also demonstrated
      functional interactions with the opioid system, where I2BS ligands have been shown to affect
      tolerance to morphine and alleviate some of the morphine withdrawal syndrome in rats.
      Recently the I2BS and I2BS ligands have been shown to have some interesting analgesic effects
      in different models of pain and a novel I2BS ligand, CR4056, is currently undergoing Phase II
      clinical trials as a novel treatment for neuropathic pain and acute non- specific pain
      states.

      The location of I2BS on astrocytic glial cells and the possibility that they may in some way
      regulate glial fibrillary acidic protein have led to increased interest into the role of I2BS
      and I2BS ligands in conditions characterised by marked gliosis. The number of I2BS has been
      shown to increase in Alzheimer's disease post mortem, and it has also been suggested that
      I2BS may be a marker for the severity and malignancy of human glioblastomas.

      The lack of suitable imaging tools for the I2BS has meant that information regarding the
      number and distribution of I2BS in the brain has come from preclinical species and in vitro
      post-mortem studies. The recent development of [11C]BU99008 as a suitable PET ligand to
      quantify I2BS in vivo, enables the direct quantification of I2BS availability and regional
      distribution in the living human brain. In this study the investigators plan to utilise
      [11C]BU99008 to quantify the regional brain availability of I2BS in the human brain in vivo
      using PET.
    

Detailed description: 
      This study will consist of three parts; Part A, B and C. Part A will involve up to 10 healthy
      subjects in order to determine the number and regional location of I2BS in healthy human
      brain following administration of [11C]BU99008. In Part B up to 6 healthy subjects will be
      recruited to provide sufficient PET data to quantify the intra- and inter-subject variability
      in the regional expression of I2BS in healthy human brain. Finally, in Part C up to 6 healthy
      subjects will be recruited in order to determine the distribution of I2BS in the whole body
      following administration of [11C]BU99008.

      The three parts of this study will be conducted in series, and only if each part is
      successful will the investigators progress to the next. This will allow us to terminate the
      study early, and hence prevent the un-necessary exposure of participants to ionising
      radiation, if the emerging data shows a clear No-go decision to progress with this PET
      ligand.

      Potential participants that pass the initial telephone screen will be invited to a screening
      visit where their eligibility to take part in the study will be determined and informed
      consent taken. This will be at the Imperial CRF and Imanova Ltd. The screening will consist
      of an interview where the study will be discussed and explained. The
      participants'understanding of the procedure, requirements and commitments confirmed and any
      questions answered before informed consent taken. In addition to this interview the
      participants personal details and demographics will be recorded and a psychiatric and medical
      history taken as well as the following:

        -  Semi-structured interviews/questionnaires will be completed: Mini International
           Neuropsychiatric Interview 5 (MINI 5), Cognitive diagnostic test for dementia (CAMCOG)

        -  A medical examination and blood taken for clinical laboratory testing.

        -  A structural MRI.

        -  Review of your medical history and current state of health, including questions about
           psychiatric symptoms and your use of prescription and non-prescription drugs, as well as
           your use of illegal drugs and alcohol.

        -  Physical examination such as measurements of blood pressure and heart rate, ECG.

        -  Collecting a urine sample to check for presence of drugs.

        -  Alcohol breath test.

        -  An "Allen's Test" will be performed to check the blood supply to your hand.

        -  Other questionnaires: Hospital Anxiety and Depression Scale (HADS), Eysenck personality
           (revised) (EPQ-R25), Spielberger Trait Anxiety Inventory (STAI), and MRI safety
           Participants that are eligible will then be invited to take part in the study, either
           Parts A, B or C as detailed below.

      Below is the intended schedule of scanning for this study. However, if for some reason it is
      necessary to cancel or suspend a scan due to radioligand production failure, scanner failure,
      etc., the participant will be asked to return on another day to. This will only happen if
      they have not had the radioligand administered by the time the study is suspended. As
      detailed below cannulae will be introduced to collect blood for various analysis on the study
      days (approximately 120 mL). The blood collected for any one participant will not exceed 500
      mL for the entire study.

      Part A

      This will be a study in healthy volunteers, and will involve up to 10 healthy human subjects,
      with each subject required to receive up to three PET scans over two study days:

        -  Scanning Day 1; Morning - baseline scan with [11C]BU99008 alone to determine the total
           number of binding sites (total, PET signal).

        -  Scanning Day 1; Afternoon - blocking scan with [11C]BU99008 in combination a single dose
           of idazoxan (I2BS block) • Scanning Day 2; All day - blocking scan with [11C]BU99008 in
           combination a single dose of isocarboxazid (MAO block) The combination of all three
           scans will allow us dissect out the regional contribution of the I2BS and MAO components
           to the [11C]BU99008 specific signal, in order to get an accurate determination of the
           number of I2BS in different brain regions. The investigators are confident that any
           component of the [11C]BU99008 signal due to MAO will be negligible. If this is confirmed
           the second scanning day will be discontinued. This adaptive approach will allow us to
           minimise unnecessary exposure of the participants to ionising radiation and study
           medication.

      Scanning day 1 - The participants will arrive at Imanova's scanning facility in the
      Burlington Danes Building, Hammersmith Hospital in the early morning. The exact time will be
      determined by the logistical constraints for two productions of [11C]BU99008. On arrival,
      participants will be asked if they agree to carry on participating in the study and their
      general health and compliance to study specific restrictions assessed by interview, urine
      drugs of abuse screen and breathalyser. Once it is confirmed they are eligible to proceed,
      they will be undergo the various procedures for that day.

      The participants will be cannulated in the radial artery and have a venous cannula inserted
      in the forearm or cubital veins. The arterial cannula is required for arterial blood sampling
      throughout the scan. A venous cannula is required for the administration of [11C]BU99008. If
      the on-going analysis indicates that arterial blood samples are not required for the analysis
      of [11C]BU99008, then these samples will not be taken from future subjects participating in
      this study and the cannula not implanted.

      Baseline subjective and objective measures will be taken before they are prepared and
      positioned in the scanner for PET scan 1. The scan will be approximately 120 min in length,
      during which time heart rate and blood pressure will be monitored. At the end of the scan,
      the participants will be removed and another set of subjective and objective measures taken.
      They will be given an acute dose of idazoxan (up to 80 mg; p.o.) about 120 min before the
      start of PET scan 2 and another round of subjective and objective measures and arterial blood
      samples taken as in PET scan 1. At the end of PET scan 2, the participant will be removed
      from the scanner, any indwelling cannulae removed, a final round of subjective and objective
      measures recorded, and their fitness to be sent home assessed by the attending physician.
      When they are fit to leave they will be sent home in a taxi.

      Scanning day 2 - The day will be similar to scanning day 1 but there will only be the one
      scan (PET scan 3). Participants will arrive at Imanova's scanning facility in the Burlington
      Danes Building, Hammersmith Hospital. Unlike scanning day 1 the time of arrival will be
      flexible, the exact arrival time will be determined by synthesis of the [11C]BU99008 and the
      most convenient time for the participant. On arrival, participants will be asked if they
      agree to carry on participating in the study and their general health and compliance to study
      specific restriction assessed by interview, urine drugs of abuse screen and breathalyser.
      Once it is confirmed they are eligible to proceed the participants will be cannulated as
      before (if required). Baseline subjective and objective measures will be taken and they will
      be administered an acute dose of isocarboxazid (up to 50 mg; p.o.) about 240 min before the
      start of PET scan 3. A round of subjective and objective measures will be recorded before
      they are prepared and positioned in the scanner for PET scan 3 (as above). At the end of the
      scan the participant will be removed from scanner, any indwelling cannulae removed, a final
      round of subjective and objective measures recorded, and their fitness to be sent home
      assessed by the attending physician. When they are fit to leave they will be sent home in a
      taxi.

      Part B

      This part of the study is to understand how the intra- and inter-subject variability in the
      I2BS regional density differs in a healthy population. To assess this, up to 6 healthy
      volunteers will receive two scans of [11C]BU99008 alone, on two separate study days:

        -  Scanning Day 1 - scan with [11C]BU99008 alone

        -  Scanning Day 2 - scan with [11C]BU99008 alone The combination of these two scans will
           enable us to determine both the intra- and inter-subject variability for the expression
           of the I2BS in a normal population.

      On arrival, participants will be asked if they agree to carry on participating in the study.
      In addition, the general health and compliance of participants to study specific restriction
      will be assessed by interview, urine drugs of abuse screen and breathalyser. The participants
      will be cannulated as described above (if required). Baseline subjective and objective
      measures will be taken prior to preparation and positioning in the scanner for the PET scan.
      The scan will be approximately 120 min in length during which heart rate and blood pressure
      will be monitored. In addition, as in Part A, arterial and/or venous blood samples will be
      taken throughout the scan. At the end of the scan the participants will be removed from the
      scanner, any indwelling cannulae removed and a final round of subjective and objective
      measures recorded. At this point the fitness of participants to be sent home will be assessed
      by the attending physician. When they are fit to leave they will be sent home in a taxi.

      Part C This part of the study is to determine the whole body bio-distribution of the I2BS in
      healthy humans. Up to 6 healthy subjects will be enrolled into this part of the study to
      determine the number and distribution of the I2BS in a variety of tissues and organs. Each
      participant will receive one whole body PET scan of [11C]BU99008. This whole body scan will
      enable us to determine how the I2BS is distributed in tissues and organs in addition to the
      brain. Participants in this part of the study will receive only one PET scan on their single
      study visit. On arrival participants will be asked if they agree to carry on participating in
      the study. In addition, the general health and compliance of participants to study specific
      restriction will be assessed by interview, urine drugs of abuse screen and breathalyser. The
      participants will be cannulated as above. Baseline subjective and objective measures will be
      taken prior to preparation and positioning in the scanner for the PET scan. The scan will be
      probably be 240 min in length (two, 2hr sessions with a break in-between) during which heart
      rate and blood pressure will be monitored. In addition, as in Parts A and B, arterial blood
      samples will be taken throughout the scan. Unlike the PET scans for Parts A & B this scan
      will occur over the whole body scan and not just the brain. At the end of the scan the
      participants will be removed from the scanner, any indwelling cannulae removed and a final
      round of subjective and objective measures recorded. At this point their fitness to be sent
      home will be assessed by the attending physician. When they are fit to leave they will be
      sent home in a taxi.
    

Intervention name(s): [11C]BU99008; Idazoxan; Isocarboxazid
Intervention type(s): Radiation; Drug; Drug
Intervention description(s): Baseline Scan, Test-ReTest or Dosimetry; Idazoxan block of [11C]BU99008; Isocarboxazid block of [11C]BU99008
Intervention MeSH terms: Isocarboxazid; Idazoxan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Imidazoline Receptor 2; (4,5-dihydro-1H-imidazol-2-yl)-1-methyl-1H-indole; BU99008; Radionuclide Imaging; Molecular Imaging; Healthy Volunteers; Alzheimer Disease