[11C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET

Abstract

The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.

A radiometabolite study of the serotonin transporter PET radioligand [11C]MADAM

“…As it has already been shown in previous non-human primate PET studies [18], the regional distribution of radioactivity in the brain following administration of [ 11 C]MADAM was consistent with the known regional densities of SERT sites. Following the administration of [ 11 C]MADAM a total brain uptake of approximately 6% of the injected dose was measured ( Figure 4A).…”

“…Among them, [ 123 I]ADAM is the current SPECT radioligand [10][11][12] and for PET studies, [ 11 C]DASB and [ 11 C]MADAM ( Figure 1) have been shown to be appropriate radioligands for the in vivo investigation of SERT [13][14][15][16][17][18][19]. this radioligand [18,19]. The percentage of the unchanged radioligand [ 11 C]MADAM in human plasma was about 40% at 50 min after radioligand injection [19].…”

Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder

“…[ 11 C]MADAM binds selectively to 5-HTT (Halldin et al 2005; Lundberg et al 2005), has good reliability in measurements of 5-HTT binding in vivo in the human brain (Lundberg et al 2006) and has been shown to be suitable for occupancy studies (Lundberg et al 2007 a ). …”

Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

“…regulation gene transcription)[ 18 F]setoperoneBlin et al [6][ 18 F]altanserinLemaire et al [14][ 11 C]MDL-100907Lundkvist et al [15][ 18 F]MH.MZHerth et al [10]5-HT 4 Excitatory receptor[ 11 C]SB207145Marner et al [17]SERTReuptake transporter (e.g. target SSRI)[ 11 C]McN5652Suehiro et al [24][ 11 C]DASBHoule et al [11][ 11 C]MADAMHalldin et al [9][ 18 F]ADAMMa et al [16]TrpPrecursor 5-HTP and substrate TPHα-[ 11 C]methyltryptophanDiksic et al [7]5-HTPPrecursor 5-HT and substrate AADC5-hydroxy- L -[β- 11 C]tryptophanBjurling et al [5]…”