Drug action at the 5-HT1A receptor in vivo: Autorecepror and postsynaptic receptor occupancy examined with PET and [carbonyl-C-11]WAY-100635

Serotonin(1A) (5-HT1A) receptors have been implicated in the pathophysiolog y and treatment of anxiety and depression and are a target for novel drug d evelopment. In this qualitative study, positron emission tomography (PET) a nd [carbonyl-C-11]WAY-100635 were used to assess 5-HT1A autoreceptor and po stsynaptic receptor occupancy in man in vivo by five different compounds wi th nanomolar affinity for this site. Occupancy by pindolol, penbutolol, bus pirone, EMD 68843, and S 15535 was compared to test-retest data from 10 hea lthy volunteers. All drugs, apart from buspirone, displayed occupancy at th e 5-HT1A receptor site. Pindolol demonstrated a preferential occupancy at t he autoreceptor compared to the postsynaptic receptor over a plasma range o f about 10-20 ng/mL. Differential occupancy may be an important component o f novel drug action. The level of autoreceptor or postsynaptic occupancy ne eded to achieve significant physiological effects is not known, although it is of note that none of the drugs in this study achieved occupancies beyon d 60%. Overall this study demonstrates the utility of PET in aiding novel d rug development. NUCL MED BIOL 27;5:509-513, 2000. (C) 2000 Elsevier Scienc e Inc. All rights reserved.