Test-retest of the newly developed P-gp PET tracer [11C]phenytoin in healthy volunteers

Resistance to current drug therapy is an issue for approximately 30% of all
people who develop epilepsy. Consequently, there is a pressing need to develop
new and more effective treatments. P-glycoprotein (P-gp) is an efflux
transporter (member of the multi-drug resistance (MDR) family), which is
located at the blood-brain barrier (BBB) and transports substrates (including
multiple CNS drugs) from brain to blood and cerebrospinal fluid. Overexpression
of P-gp is thought to be an important mechanism of pharmacoresistance in
epilepsy. Various invasive techniques used in animal studies of epilepsy showed
upregulation of P-gp. At present upregulation of P-gp in refractory patients
can only be confirmed by examining brain tissue post-mortem or after surgical
removal. Therefore availability of non-invasive imaging methods that would
allow for an assessment of distribution and function of P-gp in the brain is of
vital importance. At present only (R)-[11C]verapamil is available for assessing
P-gp function using PET. Verapamil is a substrate of P-gp and therefore
cerebral concentration is low. In case of upregulation of P-gp, it is likely
that the signal will be reduced, but this is difficult to assess due to the low
signal to noise ratio. Consequently, (R)-[11C]verapamil is not an ideal ligand
for assessing P-gp (over)expression. Therefore novel PET probes, designed to
specifically measure P-gp upregulation, need to be developed. Phenytoin is a
P-gp substrate. Recently, this compound was labelled with carbon-11, making it
a potential tool for measuring P-gp function. The first step to evaluate this
tracer is a test-retest brain-PET study in healthy volunteers.

(1) To assess [11C]phenytoin plasma and brain kinetics in healthy volunteer(s),
including assessment of the presence of radioactive metabolites in plasma. (2)
To develop a tracer kinetic model for [11C]phenytoin in humans. (3) To
determine intra-subject variation of [11C]phenytoin kinetics in humans.

Test-retest study of [11C]phenytoin in humans.

1) Radiation exposure. The exact radiation exposure of [11C]phenytoin is not
yet known. The expected radiation burden is primarily determined by the
half-life of C-11. Based on experience with 20 other C-11 labelled ligands, it
is known that the radiation exposure for a standard 370 MBq injection is
between 0.4 and 4.1 mSv (0.001-0.011 mSv/MBq), with an average of 2 .5mSv,
which is well below the accepted safety limit for human studies. The radiation
exposure of a low-dose CT of the head is 0.25mSv. For comparison, the natural
background radiation dose in the Netherlands gives annual dose of 2 * 2.5 mSv.
Thus, the total radiation exposure of the total PET procedure, based on
experience with other C-11 labelled ligands is expected to be within an
acceptable range. 2) Idiosyncratic reaction to the tracer. Due to the fact that
only sub-pharmacological doses of [11C]phenytoin are administered in PET
studies, no [11C]phenytoin-induced side-effects will be expected in this study.
A physician or physician-assistant will be present during PET scanning. 3)
Intravenous and intra-arterial cannulation There is a very small risk of
infection and bleeding associated with intravenous and intra-arterial
catheters, which are prevented by proper techniques. The venous cannulas will
be placed by qualified employees of the Department of Nuclear Medicine & PET
Research and/or employees of the department of Anesthesiology. However,
occasionally these cannulas may cause a haematoma. 4) Blood sampling. Adverse
effects of blood sampling will be minimised by exclusion of subjects with low
haemoglobin levels No more than 500 ml blood will be withdrawn during the total
PET procedure and screening. Subjects are excluded if 3 months before the PET
procedure substantial blood loss or a blood donation has occurred. Subjects are
advised not to give blood until 3 months after the scan has been completed. 5)
Discomfort during scanning. It may be uncomfortable to lie motionless in the
cameras (both PET and MRI) and it may cause some subjects to feel anxious.
Subjects will be made acquainted with the surroundings beforehand. Our staff
will be available to provide support, reduce anxiety, optimise the comfort of
the subject and remove the subject from the scanner if requested.