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PET-Determination of Robalzotan (NAD-299) Induced 5-HT1A

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PET-Determination of Robalzotan (NAD-299) Induced 5-HT1A PET-Determination of Robalzotan (NAD-299) Induced 5-HT1A Receptor Occupancy in the Monkey Brain Lars Farde, M.D., Ph.D, Bengt Andrée, M.D., Nathalie Ginovart, Ph.D., Christer Halldin, Ph.D., and Seth-Olov Thorberg, Ph.D. The serotonin 5-hydroxytryptamine-1A (5-HT1A) receptor occupancy was calculated using an equilibrium-ratio subtype is of central interest in research, particularly in the analysis. Robalzotan occupied 5-HT1A receptors in a dose- area of pathophysiology and pharmacological treatment of dependent and saturable manner. The highest 5-HT1A psychiatric disorders. Robalzotan (generic name for NAD- receptor occupancy (70–80%) was attained after 100 ␮g/kg. 299) is a new putative drug that binds with high selectivity The relationship between robalzotan drug concentration and affinity to 5-HT1A-receptors in the rodent brain in vitro and 5-HT1A receptor occupancy could be described by a and in vivo. The aim of this positron emission tomography hyperbolic function, which can be used to guide the study was to determine 5-HT1A receptor occupancy in the selection of appropriate doses for the initial studies in man. cynomolgus monkey brain in vivo after IV injection of The study further corroborates that quantitative robalzotan. Two healthy monkeys were examined with neuroimaging of receptor binding has potentials for the Positron Emission Tomography (PET) and the radioligand evaluation and dose finding of new CNS drugs. [carbonyl-11C]WAY-100635, the first after IV [Neuropsychopharmacology 22:422–429, 2000] administration of 2 ␮g/kg and 20 ␮g/kg, and the second © 2000 American College of Neuropsychopharmacology. ␮ ␮ after 10 g/kg and 100 g/kg IV. 5-HT1A receptor Published by Elsevier Science Inc. KEY WORDS: 5-HT1A receptors; Robalzotan; NAD-299; is of central interest as a target for the treatment of psy- Antidepressive & Anxiolytic drugs; Monkey brain; chiatric disorders (Saxena 1995). 11 [carbonyl- CJWAY-100635; Positron Emission Presynaptic 5-HT1A receptors mediate inhibition of Tomography 5-HT release and are highly concentrated on the cell Serotonergic neurotransmission includes distinct 5-hydroxy- bodies in the raphe nuclei (Romero et al. 1994). This re- tryptamine (5-HT) receptor subtypes, classified within ceptor has been given a key role in current hypotheses at least seven separate families (Hoyer et al. 1994; Per- on the treatment of anxiety and depression (Artigas et outka and Howell 1994). The 5-HT receptor belongs al. 1994; Baldwin and Rudge 1995; Berendsen 1995). An 1A Ϫ to the family of G-protein coupled 5-HT -receptors and important observation is that ( )pindolol, a compound 1 ␤ with affinity for -adreno-and 5-HT1A receptors, antag- onizes 5-HT1A-mediated response in the raphe nuclei (Hjorth and Carlsson 1986; Oksenberg and Peroutka From the Karolinska Institutet, Stockholm, Sweden (LF, BA, NG, CH); and AstraZeneca AB, Södertälje, Sweden (S-OT). 1988). Interestingly, pindolol may facilitate improve- Address correspondence to: Lars Farde, M.D., Ph.D., Karolinska ment of depressive patients by reducing the latency and Institutet, Department of Clinical Neuroscience, Psychiatry Section, enhancing the response rate to certain selective seroto- Karolinska Hospital, S-171 76 Stockholm, Sweden. Received July 7, 1999; revised September 7, 1999; accepted Sep- nin reuptake inhibitors (SSRI) (Artigas et al. 1994; Blier tember 17, 1999. and Bergeron 1995). An augmenting or accelerating ef- NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 4 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00125-6 NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 4 Robalzotan (NAD-299) Monkey Brain Pet Study 423 fect of pindolol has recently been confirmed in some MATERIALS AND METHODS placebo-controlled clinical studies (Perez et al. 1997; Tome et al. 1997; Zanardi et al. 1997), although negative This study was performed at the Department of Clinical results have also been reported (Berman et al. 1997; Neuroscience at the Karolinska Hospital after approval McAskill et al. 1998; Moreno et al. 1997; Perez et al. by the Animal Ethics Committee of Northern Stock- 1999). In another PET study, we have recently reported holm. Principles of laboratory animal care (NIH publi- that pindolol binds specifically to 5-HT1A receptors in cation No. 85–23, revised 1985) were followed). the living human brain (Andrée et al. 1999). This lends further support for a specific action and possible clini- Compound cal implications of pindolol treatment. Postsynaptic 5-HT1A receptors have been found in Robalzotan (NAD-299) was obtained from AstraZeneca high densities in the hippocampus and in the superfi- AB, Södertälje, Sweden. The solutions of NAD-299 were cial layers of the neocortex in man (Hall et al. 1997; Ma- prepared as an intravenous stock-solution (0.4 ␮mol/ razziti et al. 1994; Pazos et al. 1987). The high density of ml) batch 2230–4–1 according to GLP routines. postsynaptic 5-HT1A receptors in the neocortex is of in- terest in schizophrenia research, since several studies Radiochemistry have reported elevated 5-HT receptor binding in the neocortex and the hippocampus of post-mortal schizo- [carbonyl-11C]WAY-100635 was prepared by 11C acyla- phrenic brains (Burnet et al. 1996; Gurevich and Joyce tion of the precursor WAY-100634 with [carbonyl-11C]- 1997; Hashimoto et al. 1991,1993; Joyce et al. 1993; Sum- cyclobexanecarbonyl chloride, as previously described iyoshi et al. 1996). However, the antipsychotic potential in detail (Hall et al. 1997; Pike et al. 1996). The specific ␮ of selective 5-HT1A receptor antagonists or agonists has radioactivity was about 2000 Ci/mmol (74 GBq/ mol) not been explored in man. at EOS (end of synthesis). The radiochemical purity was Robalzotan with the substance name NAD-299, (R)- higher than 99%. 3-N,N-dicyclobutylamino-8-fluoro-3,4,dihydro-2H-1- benzopyran-5-carboxamide hydrogen (2R,3R)-tartate Robalzotan (NAD-299) Concentration in Plasma monohydrate), is a novel compound with high selectiv- ity and affinity (0.6 nM) to 5-HT1A-receptors in the ro- Venous blood samples (1–2 ml) were drawn from a dent brain in vitro and in vivo (Larsson et al. 1998; Sten- femoral vein, before drug administration (0 minutes), at fors et al. 1998). Functional and behavioral studies with start of the PET measurement (20 minutes) and at about robalzotan indicate antagonistic activity at the 5-HT1A- 40, 60, 80, and, after the time for the highest doses, 100 receptor (Johansson et al. 1997). The safety and tolera- minutes. The exact timing was dependent on success bility of robalzotan is currently examined in healthy with the venopuncture at each sampling. The mean subjects. plasma concentration values (Cpl.mean), determined for [carbonyl-11C]WAY-100635 is a suitable radioligand the time-interval 40–60 minutes after drug administra- for quantitative determination of 5-HT1A receptors in tion, were calculated and used for the determination of the monkey and human brain in vivo using positron the hyperbolic function between plasma concentrations emission tomography (PET) (Farde et al. 1997, 1998; and 5-HT1A receptor occupancy. NAD-299 was isolated Pike et al. 1996). This suitability has been supported by from monkey plasma samples by liquid-liquid extrac- autoradiography studies, in which the radioligand tion and analyzed by reversed phase liquid chromatog- [3H]WAY-100635 has been used for the characterization raphy (LC) combined with atmospheric pressure chem- of the 5-HT1A receptor distribution in vitro (Hall et al. ical ionization (APCI) mass spectrometry (MS). Standard 1997; Pazos et al. 1987) showing a consistent result for samples, prepared in monkey plasma, were used for the the regional 5-HT1A receptor distribution as that shown calibration curves. An automated LC-MS-MS system al- in the living human brain by PET. lowing unattended over-night operation was used. The aims of this PET study were to determine 5-HT1A NAD-299 could be reliably measured down to 0.2 nM. receptor occupancy in the cynomolgus monkey brain in See Figure 1. vivo after IV injection of robalzotan, and to establish the hyperbolic function between plasma concentration and The PET System receptor occupancy. Two healthy monkeys were exam- ined with PET and the radioligand [carbonyl-11C]WAY- The PET system used (i.e., Siemens ECAT Exact HR47), 100635, the first after administration of 2 ␮g/kg and 20 has a spatial resolution in the imaging plane of about ␮g/kg and the second after 10 ␮g/kg and 100 ␮g/kg 3.8 mm FWHM (Full Width at Half Maximum) (Wien- IV. 5-HT1A receptor occupancy in the neocortex and the hard et al. 1994). The system was used in the three- raphe nuclei were calculated using an equilibrium-ratio dimensional mode and images were displayed in 47 analysis with the cerebellum as reference region. horizontal sections. Radioactivity in the brain was mea- 424 L. Farde et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 4 Figure 1. Structural formulas of Robalzotan (NAD-299) (left) and [carbonyl-11C]WAY-100635 (right). sured continuously according to a pre-programmed se- cortex, the raphe nuclei, and the cerebellum. The ana- quence of frames for up to 93 minutes after injection of tomical delineation of regions was guided by an atlas [carbonyl-11C]WAY-100635. See Figure 2. showing a series of horizontal sections of a cynomolgus monkey brain in situ obtained by serial cryomicrotomy (Karlsson et al. 1993). PET Studies on Monkeys Two cynomolgus monkeys with a weight of 3–4 kg were obtained from the National Laboratory of Bacteri- Calculation of 5-HT1A Receptor Occupancy by the ology, Solna, Sweden. Anesthesia was induced by re- Ratio Method peated IM injection of ketamine (Ketalar® 5–10 mg kgϪ1 Ϫ Regional radioactivity was determined for each ROI h 1).
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