Test-retest of the newly developed P-gp PET tracer [11C]laniquidar 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 overexpression 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 expression, need to be developed. Laniquidar is a
P-gp antagonist and therefore it should bind in a dose dependent manner.
Recently, this compound was labelled with carbon-11, making it a potential tool
for measuring P-gp expression. Initial results of brain uptake of
[11C]laniquidar in rat were inconclusive. The rat biodistribution studies in
peripheral organs showed the highest uptake in the spleen, heart, kidney and
lung. This might be due to the formation of labelled metabolites. Nevertheless,
as the metabolite profile of (R)-[11C]verapamil is completely different between
humans and rats, only direct studies in humans can be used to determine whether
[11C]laniquidar is a potent tracer to assess P-gp expression in vivo.
Furthermore, paired [11C]laniquidar scans are needed to determine intra-subject
variation of [11C]laniquidar plasma and brain kinetics of [11C]laniquidar.

(1) To assess [11C]laniquidar 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]laniquidar in humans.

(3) To determine intra-subject variation of [11C]laniquidar kinetics in humans.

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

1) Radiation exposure.
The radiation exposure of 370 MBq [11C]laniquidar is approximately
2milliSievert (mSv). Therefore, each patient will receive a total radiation
dose of 4 mSv. 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 is within an acceptable range. In case of
previous exposure to radioactivity, subjects will be eligible if the yearly
cumulative dose due to exposure to radiation remains below 10 mSv.

2) Idiosyncratic reaction to the tracer.
Due to the fact that only sub-pharmacological doses of [11C]laniquidar are
administered in PET studies, no [11C]laniquidar-induced side-effects will be
expected in this study. A physician 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.