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.) [F-18]flumazenil via standard nucleophilic radiotluorination of the corresponding nitro-analog Ro 15-2344 has been developed. The labeling was performed by employing the (KF)-F-18/kryptofix complex in DNIF at 160 degrees C for 30 min and equimolar ratio [K/K2.2.2]F-+18(-)/precursor. Under these conditions, an F-18 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 [F-18]flumazenil as for [C-11]flumazenil. In blocking experiments, almost all radioactivity was inhibited by the addition of unlabeled flumazenil. [F-18]Flumazenil is a suitable radioligand for PET assessment of the BZR. (c) 2005 Elsevier Inc. All rights reserved.