Radioiodinated nordiazepam analog for in vivo assessment of benzodiazepine receptors by single photon emission tomography

Abstract

2′-Iodo-nordiazepam (2′-IND), a nordiazepam analog iodinated at the 2′-position of the C-5 phenyl ring, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain benzodiazepine receptors by SPECT. [ 125I]2′-IND was synthesized by the halogen exchange reaction and purified by HPLC. In an in vitro competitive binding study using [ 3H]diazepam and rat cortical synaptosomal membranes, 2′-IND showed an almost equal affinity for benzodiazepine receptors as diazepam. In a saturation binding study using rat cortical synaptosomal membranes, 2′-IND displayed a K d of 1.10 nM and a B max of 1.87 pmol/mg protein. Biodistribution and metabolism studies in mice showed that [ 125I]2′-IND exhibited rapid and high accumulation in the brain, and that the cerebral uptake and distribution of this compound occurred in the intact form. Furthermore, the administration of diazepam and flumazenil reduced cortical uptake by approx. 20%, suggesting that the uptake of 2′-IND occurred at least partly in association with benzodiazepine receptors.