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.
- - 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.
- - 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.
