1. ¹Cyclotron Building, CSC, The Hammersmith Hospital, Imperial College London, London, UK
2. ²Imaging Research Solutions Ltd, The Cyclotron Building, The Hammersmith Hospital, London, UK
3. ³Head of Clinical Pharmacology, Solvay Pharmaceuticals BV, Department of Clinical Pharmacology, The Netherlands
4. ⁴PET Division, Experimental Medicine, GlaxoSmithKline Pharmaceuticals, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK

Correspondence: Dr RA Bantick, Wellcome Clinical Research Training Fellow, Cyclotron Building, CSC, The Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 0NN, UK. Tel: +44-208-383-3160; Fax: +44-208-383-1783; E-mail: rabantick@doctors.org.uk

Received 27 July 2003; Revised 7 December 2003; Accepted 18 December 2003; Published online 25 February 2004.

Abstract

Drugs acting on the 5-HT_1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT_1A receptor occupancy by the 5-HT_1A agonist drugs flesinoxan (a highly selective probe for the 5-HT_1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT_1A antagonist radiotracer [¹¹C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [¹¹C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT_1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (1 SD) for flesinoxan was 8.7% (13%), and for ziprasidone 4.6% (17%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17–57%) at 0.25 mg/kg and above. We conclude that 5-HT_1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT_1A antagonists bind equally to low- and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.