Preparation of highly specific radioactivity [ 18F]flumazenil and its evaluation in cynomolgus monkey by positron emission tomography

A straightforward method for the preparation of no-carrier-added (n.c.a.) [ 18F]flumazenil via standard nucleophilic radiofluorination of the corresponding nitro-analog Ro 15-2344 has been developed. The labeling was performed by employing the K 18F/kryptofix complex in DMF at 160°C for 30 min and equimolar ratio [K/K2.2.2] +18F −/precursor. Under these conditions, an 18F incorporation rate into flumazenil was in the range of 55–60%. The final product was isolated by HPLC purification within a total synthesis time of 75 min and a radiochemical yield of about 30% (EOB). Human post-mortem whole-hemisphere autoradiography of brain sections demonstrated selective uptake of the radioligand in the areas of high density of the central benzodiazepine receptors (BZR). PET studies in a cynomolgus monkey and metabolite studies by HPLC demonstrated similar results by [ 18F]flumazenil as for [ 11C]flumazenil. In blocking experiments, almost all radioactivity was inhibited by the addition of unlabeled flumazenil. [ 18F]Flumazenil is a suitable radioligand for PET assessment of the BZR.