Onderzoek ter evaluatie van de test -retest variatie van [11C]fenytoine in gezonde vrijwilligers.

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, overexpression of P-gp in refractory patients has only been confirmed by examining brain tissue post-mortem or after surgical removal without resulting in direct information on P-gp functionality. Availability of non-invasive imaging methods that would allow for an in vivo assessment of distribution and function of P-gp in the brain is of vital importance.
At present only (R)-[11C]verapamil is routinely used for assessing P-gp function using PET. Verapamil is a substrate of P-gp and therefore cerebral concentrations are low. In case of upregulation of P-gp, it is likely that the signal will be reduced even further, but this is difficult to assess due to the low signal to noise ratio. The signal to noise ratio is even further reduced by cerebral uptake of radiolabelled metabolites of (R)-[11C]verapamil.

Consequently, (R)-[11C]verapamil is not an ideal ligand for assessing P-gp function. Therefore novel PET probes, designed to specifically measure P-gp function, need to be developed.

It has been shown that phenytoin is a substrate of P-gp. Recently, phenytoin was labelled with carbon-11. PET studies in rats have shown that [11C]phenytoin has more favourable characteristics for measuring P-gp function than (R)-[11C]verapamil: First, [11C]phenytoin has a higher initial brain uptake in rats than (R)-[11C]verapamil, so an upregulation of P-gp would be easier to detect. Second, in animal experiments [11C]phenytoin has shown optimal brain kinetics, i.e. fast transport into the brain, reaching equilibrium well within the time span of a PET scan with an ideal rate of clearance (not too slow, not too fast) from the brain. Third, in rats, [11C]phenytoin is metabolically more stable than (R)-[11C]verapamil in both brain and plasma, causing less problems with labelled metabolites. Nevertheless, as the metabolite profile of (R)-[11C]verapamil in humans is completely different from that in rats, only direct studies in humans can determine whether [11C]phenytoin is indeed a more potent tracer to assess P-gp function in vivo. Furthermore, paired [11C]phenytoin scans are needed to determine inter- and intra-subject variation of [11C]phenytoin plasma and brain kinetics of [11C]phenytoin.



Volunteers will be recruited only in the Netherlands, mainly with some relation to the VU medical center.

Primary Objectives:

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 inter- and intra-subject variation of [11C]phenytoin kinetics in humans.

Positron Emmisson Tomography (PET) will be applied during after administration of the radiotracer [11C]phenytoin. This will be repeated on the same day.The complete procedure takes one day (9-17hr) per volunteer.

Data will be analysed off-line and final anlysis of the inter-and itra-individualvariability will take place after scanning all volunteers.

This is a single-centre test-retest study in healthy humans. We will include (at least) 12 healthy subjects to obtain 12 evaluable test-retest [11C]phenytoin PET scans. These subjects will receive paired [11C]phenytoin PET scans on one day at the Department of Nuclear Medicine & PET Research of the VUmc. All subjects will also undergo an MRI scan for localisation purposes that will be performed at the department of Radiology of the VUmc.