The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by positron emission tomography

Abstract

Positron emission tomography (PET) and 11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D2 receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean +/- 2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.

The Differential Effects of Atypical Antipsychotics on Prolactin Elevation Are Explained by Their Differential Blood-Brain Disposition: A Pharmacological Analysis in Rats

“…All these studies have established a relationship between higher D2 occupancy and higher prolactin elevation (Nordstrom et al, 1992;Bench et al, 1996;Kapur et al, 2000). However, the precise level at which striatal occupancy begins has varied considerably from one drug to the other (Nordstrom et al, 1992;Bench et al, 1996;Kapur et al, 2000). Given the severalfold variation across antipsychotics with reference to their central to peripheral ratios shown here, it is not surprising that no absolute relationship between central occupancy and prolactin elevation has been or could logically be shown.…”

“…Nonetheless, several researchers have used striatal D2 occupancy as a proxy measure of pituitary occupancy and attempted to relate prolactin elevation to striatal D2 occupancy. All these studies have established a relationship between higher D2 occupancy and higher prolactin elevation (Nordstrom et al, 1992;Bench et al, 1996;Kapur et al, 2000). However, the precise level at which striatal occupancy begins has varied considerably from one drug to the other (Nordstrom et al, 1992;Bench et al, 1996;Kapur et al, 2000).…”

Occupancy of Agonist Drugs at the 5-HT1A Receptor

“…Previous PET studies have established that ziprasidone penetrates the brain at the dose used in this study: high levels of occupancy have been observed at both the D 2 receptor (Bench et al, 1996) and the 5-HT 2A receptor (Fischman et al, 1996) as discussed in the introduction. Flesinoxan penetrates the brain in rats, albeit much less efficiently than the prototypical 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT (Hadrava et al, 1995).…”

“…The former effect is prevented and the latter roughly halved by the 5-HT 1A antagonist WAY-100635. In human PET studies, 40 mg oral ziprasidone occupies B72% D 2 receptors using the D 2 antagonist radiotracer [ 11 C]raclopride (Bench et al, 1996) and B95% 5-HT 2A receptors using the 5-HT 2A antagonist radioligand [ 18 F]setoperone (Fischman et al, 1996) 4-8 h post-dose. In patients with acute exacerbations of schizophrenia and schizoaffective disorder, randomized double-blind studies have shown ziprasidone to have efficacy superior to placebo (Daniel et al, 1999;Keck et al, 1998) and similar to haloperidol (Goff et al, 1998).…”

Ziprasidone 80 mg/day and 160 mg/day in the Acute Exacerbation of Schizophrenia and Schizoaffective Disorder A 6-Week Placebo-Controlled Trial

“…In healthy volunteers, positron emission computed tomography (PET) studies confirmed that the occupancy by ziprasidone of 5HT 2 receptors substantially exceeded that of D 2 receptors (Fischman et al 1996;Bench et al 1993;Bench et al 1996). In a 28-day clinical trial in which the majority of patients (84/90) had an acute exacerbation of schizophrenia or schizoaffective disorder, ziprasidone 160 mg/day reduced Brief Psychiatric Rating Scale (BPRS) total and core item scores and Clinical Global Impression of Severity (CGI-S) scores similarly to haloperidol 15 mg/day (Goff et al 1998).…”