Biodistribution and dosimetry 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) seems to be involved in drug resistance. 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 even further 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 an antagonist of P-gp 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 rats 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.
Based on these biodistribution studies, the expected dose for a standard 370
Mega Becquerel (MBq) injection would be 1.85mSv (0.005mSv/MBq), well below the
accepted safety limit for human studies.
Nevertheless, as the metabolite profile of (R)-[11C]verapamil is expected to be
completely different between humans and rats, only direct studies in humans can
be used to determine the optimal (safe) dose of [11C]laniquidar. One condition
for human use is that, in general, an injected dose of around 370 MBq is needed
to allow for accurate measurements of plasma and tissue kinetics.

(1) To assess biodistribution of [11C]laniquidar in healthy volunteers;
(2) To determine the actual effective radiation dose of [11C]laniquidar in
humans;
(3) To assess the metabolic profile of [11C]laniquidar in humans.

Single-centre biodistribution and dosimetry study in humans.

1) Radiation exposure.
A PET-CT scan is a regular diagnostic imaging technique. Each study will be
conducted in compliance with the radiation safety guidelines of the department.
Based on results we obtained from biodistribution studies in rats, we
calculated using Olinda software 26 that whole body radiation after intravenous
injection of 370 MBq [11C]laniquidar is approximately 1.8mSv. In addition a
low-dose CT scan performed during PET scanning has a radiation dose of 2-3 mSv
depending on the required CT beam current. Therefore, the subject will receive
a total radiation dose between 3.8 - 4.8 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.

After scanning one evaluable subject the effective radiation dose will be
calculated (using Olinda software26) based on the biodistribution data of this
subject. If necessary, the dose of [11C]laniquidar will be adjusted in the next
five subjects (see §3 Study design).

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 cannulation.
There is a very small risk of infection and bleeding associated with
intravenous catheters, which are prevented by proper techniques. The venous
cannulas will be placed by qualified employees of the Department of Nuclear
Medicine & PET Research. 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 100ml blood will be withdrawn during
the total PET procedure and screening.

5) Discomfort during scanning.
It may be uncomfortable to lie motionless in the PET-CT camera 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.