Abstracts

The GABA[sub]A[/sub]-receptor plays an important role in epileptogenesis. An important question is to what extent down regulation of the GABA[sub]A[/sub] receptor can explain pharmacoresistance to antiepileptic drugs. Positron Emission Tomography (PET) with [¹¹C]flumazenil ([¹¹C]FMZ) is a method that can be used to quantify the GABA[sub]A[/sub]-receptor expression [italic]in vivo[/italic]. We have developed a new quantitative method, which makes it possible to measure the receptor expression (B[sub]max[/sub]) and the affinity (K[sub]D[/sub]) simultaneously. After injection of an excess amount of FMZ, which fully saturated the receptors, the concentration time curves of FMZ in brain (using a single LSO layer HRRT PET scanner) and arterial blood (using HPLC-UV) were measured. B[sub]max[/sub] and K[sub]D[/sub] were then estimated by population Pharmacokinetic/Pharmacodynamic (PK/PD) modelling, using a 4-compartment PK model, comprising a blood, tissue and 2 brain (free and specifically bound) compartments. Population PK/PD modelling allows analysis of the data of all animals simultaneously, taking inter-individual variability of parameters into account. 24 rats were used, which received either 2000 mg (n=2), 1000 mg (n=1), 500 mg (n=7), 100 mg (n=3), 50 mg (n=3), 25 mg (n=2), or 1 mg (n=6). Simultaneous analysis of all data with the proposed model resulted in the precise estimation of the specific binding of FMZ in the brain, as characterised by B[sub]max[/sub] (32.7 [plusmn] 7.95 ng/ml) and K[sub]D[/sub] (10.1 [plusmn] 2.61 ng/ml). In conclusion a novel full saturation approach is reported, which allows simultaneous estimation of both B[sub]max[/sub] and K[sub]D[/sub] in a single experiment. This model will be used to assess changes in GABA[sub]A[/sub]-receptor properties in relation to progression of epilepsy in various experimental animal models. Moreover, this approach can also be used in human studies. (Supported by National Epilepsy Fund; grant 02-06)