Validation du [18F]-Fluoroethylflumazenil comme traceur du récepteur central des benzodiazépines en Tomographie par Emission de Positons (TEP)
(2006)
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- [11C]-Flumazenil is a well known ligand of the central benzodiazepine receptor. It has been widely used in Positron Emission Tomography (PET) for mapping gabaergic neurons and for the quantitation of BZR density. This radiotracer is also successfully used in refractory epilepsy as a diagnostic tool. [18F]-Fluoroethylflumazenil ([18]F-FEF) was proposed as an alternative to [11C]-FMZ. Our aim is to characterize the behaviour of this new tracer, ea. its metabolism, its biodistribution pattern, or its binding specificity. This constitutes a preclinical validation study. First, we developped a new HPLC analytical method in order to separate [18]F-FEF metabolites formed in vitro on liver microsomes. Tandem mass spectrometry allowed us to identify various metabolites, resulting from lateral chain hydroxylations, or dealkylation. Then we describe the in vivo biodistribution of [18]F-FEF in rodents. [18]F-FEF is mainly found in liver and in the kidneys; cerebral radioactivity level is low compared to 3H-Flumazenil level. Nevertheless [18]F-FEF binding in the brain is specific. Fast in vivo metabolisation could possibly account for this low level binding in the brain, as more than 40% of plasmatic activity is due to metabolites, three minutes only after iv administration of the tracer. Metabolites isolated in plasma do not cross the blood brain barrier since they are not found anymore in the brain. Then, we present results from healthy human volunteers and two epileptic patients suffering from mesio-temporal epilepsy. [18]F-FEF binds to cortical areas following an expected distribution, with a higher binding in BZ receptor-rich areas. Its cerebral clearence is very fast, as is the plasmatic biotransformation (T1/2=8 min). In epileptic patients, hypofixation is noted in the mesial part of the temporal lobe, which is thought to be the origin of the epileptic focus. Finally, BZR density is quantified as Distribution Volumes (DV) or Binding Potentials (BP) using various established pharmakokinetic models. A good correlation is observed between results obtained with the various models. We can conclude that [18]F-FEF has a kinetic and metabolic profile wich is less favourable than the profile of [11C]-FMZ. Nevertheles, [18]F-FEF is a specific tracer of BZR that allows quantification of BZR density with DV or BP.
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Levêque, P. (2006). Validation du [18F]-Fluoroethylflumazenil comme traceur du récepteur central des benzodiazépines en Tomographie par Emission de Positons (TEP). https://hdl.handle.net/2078.5/112211