Assessment of blood-brain barrier passage of flumazenil in patients with epilepsy.

Resistance to current drug therapy is an issue for approximately 30% for all people who develop epilepsy. Consequently,
there is a pressing need to develop new and more effective treatments.
P-gp is an efflux transporter, which is located at the BBB and transports substrates (including multiple CNS drugs) from the 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 have shown upregulation of P-gp. At present upregulation of P-gp in refractory patients can only be confirmed by examining post-mortem or surgically removed brain tissue.
Therefore the availability of non-invasive imaging methods that would allow the assessment of the distribution and function
of P-gp in the brain is of vital importance.
Currently only [11C]verapamil is available to assess P-gp function by using positron emission tomography (PET), but is
not an ideal ligand to assess P-gp expression. Novel imaging probes, which are markers for the function of P-gp need to be evaluated. Such a probe could then be used to establish a non-invasive molecular imaging-based tool which will allow evaluation of the role of P-gp for pathophysiology and treatment response in epilepsy and other major CNS diseases,
using the established imaging techniques.
One of the important goals of the project is to quantify to what extent P-gp upregulation affects the binding of an established PET ligand known to be a P-gp substrate, namely [11C]-flumazenil. Flumazenil is a ligand that binds to the GABAA-receptor, but has no agonistic or antagonistic actions on this receptor. Labeled with [11C], flumazenil is frequently used for PET scanning in epilepsy patients to assess changes in GABAA-receptor density and to determine focus localization prior to resective surgery. There is circumstantial evidence from animal and in vitro studies that flumazenil is a substrate for P-gp. If this is indeed the case, changes in P-gp expression or functionality would compromise the interpretation of GABAA-receptor binding data.

Flumazenil is a substrate of P-glycoprotein at the blood-brain barrier.

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2x [11C]flumazenil- and 2x [15O]water PET scan with one gift of Tariquidar in between.