Acute effect of 3-(4-acetamido)-butyrril-lorazepam (DDS2700) on brain function assessed by PET at rest and during attentive tasks

The aim of this study was to assess, by positron emission tomography (PET), the effect on cerebral functional activity of a new lorazepam-gamma -amino butyric acid (GABA) conjugate [3-(4-acetamido)-butyrril lorazepam (DDS2700) ]. Ten healthy volunteers were studied by PET and [F-18]fluoro-deoxy-D-gluc ose ([F-18]FDG) under baseline conditions and following the administration of DDS2700. Regional cerebral blood flow (rCBF) was measured by PET and O-1 5-water in three additional participants while they performed attentive tas ks, before and after drug administration. DDS2700 induced a decrease in the regional cerebral metabolic rate of gluco se (rCMRglu) in the thalamus (-17%), cerebellum (-11%) and caudate nucleus (-8%). The observed effects on glucose metabolism Here probably related to the subjective sedation and tiredness reported by the participants. During the attentive tasks, rCBF increased in frontal and temporal regions associa ted with attentional processing of auditory material. These circuits were n o longer active after DDS2700 administration, while rCBF increased in cingu late carter, occipitoparietal regions, pens and cerebellum. These drug-indu ced activations might be directly related to intervening sleepiness and to the consequent effort in keeping attention focused on the tasks. The effects of DBS2700 on glucose metabolism at rest, and on rCBF during ac tivation conditions, indicate a drug action on cerebral networks involved i n alertness, vigilance and attention maintenance. PET assessment by [F-18]F BG and water may provide complementary information in pharmacodynamic studi es. ((C) 2001 Lippincott Williams & Wilkins).