Biological properties of 2′-[18F]fluoroflumazenil for central benzodiazepine receptor imaging

Abstract

A novel positron emitting agent, 2′-[18F]fluoroflumazenil (fluoroethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate, FFMZ), has been reported for benzodiazepine imaging. In the present study, biological properties of [18F]FFMZ were investigated. Stability tests of [18F]FFMZ in human and rat sera were performed. Biodistribution was investigated in mice and phosphorimages of brains were obtained from rats. A receptor binding assay was performed using rat brain (mixture of cortex and cerebellum) homogenate. A static positron emission tomography (PET) image was obtained from a normal human volunteer. Although [18F]FFMZ was stable in human serum, it was rapidly hydrolyzed in rat serum. The hydrolysis was 39%, 63% and 92% at 10, 30 and 60 min, respectively. According to the biodistribution study in mice, somewhat even distribution (between 2∼3% ID/g) was observed in most organs. Intestinal uptake increased up to 6% ID/g at 1 h due to biliary excretion. Bone uptake slowly increased from 1.5% to 3.5% ID/g at 1 h. High uptakes in the cortex, thalamus and cerebellum, which could be completely blocked by coinjection of cold FMZ, were observed by phosphorimaging study using rats. Determination of Kd value and Bmax using rat brain tissue was performed by Scatchard plotting and found 1.45±0.26 nM and 1.08±0.03 pmol/mg protein, respectively. The PET image of the normal human volunteer showed high uptake in the following decreasing order: frontal cortex, temporal cortex, occipital cortex, cerebellum, parietal cortex and thalamus. In conclusion, the new FMZ derivative, [18F]FFMZ appears to be a promising PET agent for central benzodiazepine receptor imaging with a convenient labeling procedure and a specific binding property.