POSITRON EMISSION TOMOGRAPHIC ANALYSIS OF CENTRAL 5-HYDROXYTRYPTAMINE(2) RECEPTOR OCCUPANCY IN HEALTHY-VOLUNTEERS TREATED WITH THE NOVEL ANTIPSYCHOTIC AGENT, ZIPRASIDONE

Ziprasidone is a novel antipsychotic agent, with high affinity for dop amine D-2 and serotonin (5-HT2) receptors in vitro and in animal model s. The goal of this study was to determine the time course of 5-HT2 re ceptor occupancy (%RO) in healthy humans after a single p.o. dose. Pos itron emission tomography with the 5-HT2 ligand, [F-18]setoperone, was performed in eight male volunteers, in the drug-naive, base-line (BL) state and 4 to 18 hr after ziprasidone (40 mg). Cerebral cortical bin ding potential [BP, maximum number of available receptors/K-D or assoc iation rate for specific binding (k(3))/dissociation rate for specific binding (k(4))] was estimated using the cerebellum as reference. Tran sport rate from plasma to brain (K-1), transport rate from brain to pl asma (k(2)), association rate of nonspecific binding (k(5)) and dissoc iation rate of nonspecific binding (k(6)) were derived by fitting cere bellar time-activity curves to a three-compartment model. Fitting of c ortical data to a 4-compartment model with K-1/k(2), k(5) and k(6), fi xed at cerebellar values, was used to determine k(3) and k(4). %RO was calculated using the relation: %RO = [(BPBL - BPDRUG/BPBL] x 100%. At BL, cortical parameter (mean +/- S.E.M) were: K-1 = 0.121 +/- 0.0072 ml . min(-1) . g(-1); k(2) = 0.0581 +/- 0.004 min(-1); k(3) = 0.321 +/ - 0.0026 min(-1); k(4) = 0.0957 +/- 0.0059 min(-1); k(5) = 0.0147 +/- 0.00066 min(-1) and k(6) = 0.0059 +/- 0.00042 min(-1). Ziprasidone did not effect K-1, k(2), k(5) or k(6); however, k(3) was reduced and k(4 ) was elevated (P < .01). RO was nearly complete at 4 hr after dosing (98%) and remained elevated at 18 hr (46%). Plasma concentrations were well described by a biexponential function and decreased much more ra pidly than RO. These results establish that ziprasidone has high poten cy for blocking 5-HT2 receptors in healthy humans; a potentially impor tant characteristic of atypical antipsychotic agents.