Owing to the lack of biologically based clinical measures and reliable biomarkers for many indications within the CNS area, the use of imaging tools, such as ligand-based positron emission tomography (PET), has become more and more important in the development of new CNS drugs. A well-grounded and reliable relationship between the plasma concentration of the drug and the occupancy of the receptor/transporter is a powerful tool to investigate the mechanism of action of a new drug and to guide dose selection in patients. Imaging of the serotonin transporter (5-HTT) by means of either PET or single photon emission computed tomography (SPECT) is one of the most useful methods in the neuro- and psychopharmacological field. A number of different ligands have been tested and used over the past 20 years. The first radiotracer ligand to be used in human beings was the SPECT ligand [123I]2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane (β-CIT), and in 1995, the first successful PET imaging study of the distribution of the 5-HTT in the brain of human volunteers using [11C](+)McN5652 (trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl]-pyrrolo-[2,1-a]-isoquioline) was reported [1]. In 2005, the first study with the PET ligand [11C]-MADAM (N,N-dimethyl-2-(2-amino-4-methylphenylthio) benzylamine) in human beings was reported [2], and the suitability of the cerebellum as a reference region for non-specific [11C]-MADAM binding could be confirmed, thus paving the way for experimentally less demanding approaches, such as the simplified reference tissue model. The ligand [11C]-DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) seems today to be the most widely used, because of its selectivity, reversibility, reliability and great specific binding [3]. A thorough review of different 5-HTT ligands has been given by Meyer [4]. A summary of the characteristics for [11C]-MADAM and [11C]-DASB is given in table 1. Lu AA21004 (1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine) is a novel compound currently in phase III testing as an antidepressant [5]. In recombinant cell lines, the multimodal antidepressant Lu AA21004 is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HTT. In non-clinical studies, Lu AA21004 increases levels of noradrenaline, dopamine, acetylcholine and histamine [6]. The affinities for the 5-HT1A, 5-HT1B, 5-HT3 and 5-HT7 receptors and the 5-HTT are all considered to be of clinical relevance and involved in the mechanism of action at therapeutic doses. In contrast to selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenalin reuptake inhibitors (SNRIs), which mainly have affinity for the 5-HTT [and noradrenalin transporter (NAT) in case of SNRIs], Lu AA21004 has a broad receptor-binding profile. During the clinical development of Lu AA21004, two PET studies have been performed using 5-HTT ligands (either [11C]-MADAM or [11C]-DASB) to quantify the 5-HTT occupancy in the brain of human subjects. The purpose of this study was to describe the 5-HTT human brain occupancy after Lu AA21004 administration and its relation to the plasma concentrations of Lu AA21004. Study designs. Data originate from two different open-label studies, performed at different sites (necessary because of subject recruitment) and with access to different 5-HTT ligands. In study A, PET measurements were taken on day 1 (i.e. after a single dose) and on day 9 of multiple dosing in 11 young healthy Caucasian subjects using the [11C]-MADAM ligand. In study B, PET measurements were taken after 13 days of multiple dosing in 35 young healthy Caucasian or Japanese subjects with the [11C]-DASB ligand. Study A investigated the 5-HTT occupancy at three dose levels of Lu AA21004 (2.5, 10 and 60 mg/day), whereas the doses in study B were 2.5, 5 and 20 mg/day. Both studies were approved by local ethics committees and were conducted in accordance with Good Clinical Practice (GCP) and the Declaration of Helsinki. The data set consisted of 46 healthy male subjects (28 Caucasian and 18 Japanese) with a mean age of 28 years (range, 21–41). The mean weight and BMI were 73 kg (range, 57–95) and 23 kg/m2 (range, 19–29), respectively. Subjects were enroled after they signed the informed consent form, and it was verified that subjects fulfilled the inclusion criteria and did not meet any exclusion criteria. Pharmacokinetic blood sampling. For study A, venous blood samples (2 mL) for the analysis of plasma content of Lu AA21004 were drawn on day 1 at 1, 2, 3, 4 and 6 hr post-dose; on days 2–8 at pre-dose; and on day 9 at 1, 2, 3, 4, 6, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 14, 24, 36, 48, 72, 96 and 120 hr post-dose. For study B, samples were drawn on day 1 at 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hr post-dose, on days 3, 5, 7, 9, 11 and 13 at pre-dose and on day 14 at 1, 2, 3, 4, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hr post-dose. The plasma concentrations of Lu AA21004 were determined using an analytical method validated in accordance with FDA guidance [7]. Lu AA21004 was extracted from plasma followed by liquid chromatography and quantified by a mass spectrometry. The BP at baseline for [11C]-MADAM had a mean (±S.D.) of 4.3 ± 1.7 and hence a coefficient of variation of 40%. For [11C]-DASB, the BP at baseline had a mean (±S.D.) of 2.2 ± 0.39 and a coefficient of variation of 18%. The 5-HTT occupancies at different dosing regimens of Lu AA21004 administration (single or multiple doses) are shown in table 2. The non-linear regression analysis relating plasma concentrations of Lu AA21004 and 5-HTT occupancy using the Emax model gave parameter values of 99% for Emax and 4.8 ng/mL for EC50. The relative standard errors (standard error divided by mean value) were 3.8% and 17%, respectively. The nature of the PET ligand had no significant impact on Emax or EC50, because the decrease in the objective function values was smaller than 7.88 for both ligands. This can also be observed in fig. 1, where the individual curve fits for two ligands are very close to each other. Likewise, race (Caucasian/Japanese) had no significant impact on Emax or EC50. In fig. 1, the plasma concentrations of Lu AA21004 are plotted against the 5-HTT occupancy values. The relationship between Lu AA21004 plasma concentration and 5-HTT occupancy. The plasma concentration of Lu AA21004 versus the observed (circles and triangles) and the estimated curve fits of the 5-HTT occupancy in the raphe nuclei region. The 95% confidence limits of the fitted curve are shown as dotted lines. Filled circles show single-dose data, while open circles and triangles show multiple-dose data. The mean BPs at baseline were 4.3 and 2.2 for [11C]-MADAM and [11C]-DASB, respectively. However, there were no significant differences in the Lu AA21004 plasma concentration-5-HTT occupancy relationship between two ligands. Neither Emax nor EC50 was influenced by which PET ligand had been used. This is consistent with a study by Elfving et al. [9], showing that the DASB and MADAM ligands had similar affinity for 5-HTT in rat and monkey brains. MADAM and DASB displayed significant specific binding to 5-HTT in monkey cerebellum, with receptor density (Bmax) cortex/cerebellum ratios of 3 and 4 for MADAM and DASB, respectively. In rat brain, the Bmax cortex/cerebellum ratios were 6 and 3 with MADAM and DASB, respectively [6]. It has been proposed that the occupancy of the 5-HTT should be around 80% for a conventional SSRI/SNRI to be therapeutically useful [4]. Lu AA21004 has been shown to be efficacious at doses of 5 and 10 mg/day in a clinical phase II proof-of-concept study in patients with major depressive disorder [10]. The plasma concentrations of Lu AA21004 at steady state for 5 mg correspond, using the relation between Lu AA21004 exposure and 5-HTT occupancy, to the 5-HTT occupancy of approximately 50%. This indicates that Lu AA21004 may be efficacious at lower 5-HTT occupancy than necessary with SSRI/SNRIs. The explanation for this may be Lu AA21004's multimodal neurotransmitter enhancer profile, where the affinity for the receptor subtypes 5-HT1A, 5-HT1B, 5-HT3 and 5-HT7 can contribute to the clinical effect. In conclusion, we have shown that Lu AA21004 occupies the 5-HTT and that the relationship between plasma exposure of Lu AA21004 and 5-HTT occupancy can be reliably described by an Emax model. All authors are employed by H. Lundbeck A/S, the sponsor of two studies. The authors have nothing to disclose.
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