[F-18]fluoroethylflumazenil: a novel tracer for PET imaging of human benzodiazepine receptors

5-(2'-[F-18]Fluoroethyl)flumazenil ([F-18]FEF) is a fluorine-18 labelled po sitron emission tomography (PET) tracer for central benzodiazepine receptor s. Compared with the established [C-11]flumazenil, it has the advantage of the longer half-life of the fluorine-18 label. After optimisation of its sy nthesis and determination of its in vitro receptor affinities, we performed first PET studies in humans. PET studies in seven healthy human volunteers were performed on a Siemens ECAT EXACT whole-body scanner after injection of 100-280 MBq [F-18]FEF. In two subjects, a second PET scan was conducted after pretreatment with unlabelled flumazenil (1 mg or 2.5 mg i.v., 3 min b efore tracer injection). A third subject was studied both with [F-18]FEF an d with [C-11]flumazenil. Brain radioactivity was measured for 60-90 min p.i . and analysed with a region of interest-oriented approach and on a voxelwi se basis with spectral analysis. Plasma radioactivity was determined from a rterial blood samples and metabolites were determined by high-performance l iquid chromatography. In human brain, maximum radioactivity accumulation wa s observed 4 +/-2 min p.i., with a fast clearance kinetics resulting in 50% and 20% of maximal activities at about 10 and 30 min, respectively. [F-18] FEF uptake followed the known central benzodiazepine receptor distribution in the human brain (occipital cortex > temporal cortex > cerebellum > thala mus > pons). Pretreatment with unlabelled flumazenil resulted in reduced tr acer uptake in all brain areas except for receptor-free reference regions l ike the pons. Parametric images of distribution volume and binding potentia l generated on a voxelwise basis revealed two- to three-fold lower in vivo receptor binding of [F-18]FEF compared with [C-11]flumazenil, while relativ e uptake of [F-18]FEF was higher in the cerebellum, most likely owing to it s relatively higher affinity for benzodiazepine receptors containing the al pha6 subunit. Metabolism of [F-18]FEF was very rapid. Polar metabolites rep resented about 50%-60% of total plasma radioactivity at 5 min and 80%-90% a t 20 min p.i. Although [C-11]flumazenil has some advantages over [F-18]FEF (higher affinity, slower metabolism, slower kinetics), our results indicate that [F-18]FEF is a suitable PET ligand for quantitative assessment of cen tral benzodiazepine receptors, which can be used independently of an on-sit e cyclotron.