Ethyl 8-fluoro-5-[11C]methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Excerpt

The development of epilepsy has been associated with the impairment of gamma-aminobutyric acid (GABA) neurotransmission in the central nervous system because a reduced GABA release has been observed in the mesial temporal lobe during epilepsy episodes in animals and a GABA-mediated inhibition loss was reported in human epileptic hippocampal sclerosis (1, 2). The GABA receptors (GABAR) comprise several different pharmacological subtypes depending on the type of subunits constituting the receptor complex, and GABA mediates its effects primarily through the GABA_A receptors (3). Also, individuals with the Angleman syndrome (AS) have a neurodevelopmental disorder that results in severe mental retardation, delayed motor development, and epilepsy (4). It has been shown that surviving gabrag3-knockout mice are epileptic and have a phenotype that is similar to AS patients, indicating that the GABRβ3 gene in humans could have a role in the development of AS (5). Interestingly, genes coding for the various GABAR subunits (β3, α5, and γ3) are located within the same 15q11-q13 region of the human chromosome that is believed to have a function in the development of AS (5, 6), suggesting that the GABARβ3 gene may have a role in the development of AS in humans. In addition, the GABA_Aknockout mice were shown to have reduced levels of the GABA_A receptor.

A benzodiazepine (BDZ) site antagonist labeled with radioactive carbon ([¹¹C]), ethyl 8-fluoro-5-[¹¹C]methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate ([¹¹C]flumazenil ([¹¹C]FMZ)), which has a high affinity for the GABA_A receptors, has been used widely with positron emission tomography (PET) for the investigation of the these receptors (7). Flumazenil is available commercially in the United States and has been approved by the United States Food and Drug Administration for use in various clinical trials.