Novel Radiotracers for Imaging the Serotonin Transporter by Positron Emission Tomography:  Synthesis, Radiosynthesis, and in Vitro and ex Vivo Evaluation of <sup>11</sup>C-Labeled 2-(Phenylthio)araalkylamines

Seasonal affective disorder (SAD) is highly prevalent with rates of 1-6% and greater prevalence at more extreme latitudes; however, there are almost no direct brain investigations of this disorder. In health, serotonin transporter binding potential (5-HTT BP ND ), an index of 5-HTT levels, is greater throughout the brain in fall-winter compared with spring-summer. We hypothesized that in SAD, this seasonal variation would be greater in brain regions containing structures that regulate affect such as the prefrontal and anterior cingulate cortices (PFC and ACC). Furthermore, given the dimensional nature of SAD symptoms, it was hypothesized that seasonal fluctuation of 5-HTT BP ND in the PFC and ACC would be greatest in severe SAD. Twenty SAD and twenty healthy participants underwent [11 C]DASB positron emission tomography scans in summer and winter to measure seasonal variation in [ 11 C]DASB 5-HTT BP ND . Seasonal increases in [11 C]DASB 5-HTT BP ND were greater in SAD compared with healthy in the PFC and ACC, primarily due to differences between severe SAD and healthy (severe SAD vs healthy; Mann-Whitney U, U = 42.5 and 37.0, p = 0.005 and 0.003, respectively; greater magnitude in severe SAD of 35.10 and 14.23%, respectively), with similar findings observed in other regions (U = 40.0-62.0, p = 0.004-0.048; greater magnitude in severe SAD of 13.16-17.49%). To our knowledge, this is the first brain biomarker identified in SAD. This creates a new opportunity for phase 0 studies to target this phenotype and optimize novel prevention/treatment strategies for SAD.

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“…Synthesis of [ 11 C]DASB has been described previously (Ginovart et al, 2001;Wilson et al, 2000). Briefly, […”

Section: Scanningmentioning

confidence: 99%

Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

Tyrer

Levitan

Houle

et al. 2016

Neuropsychopharmacol

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“…Especially, increased serotonin level in prefrontal cortex is thought to be a key step in the therapeutic mechanism of SSRIs (Bel and Artigas, 1992;Invernizzi et al, 1992Invernizzi et al, , 1996. Positron emission tomography (PET) studies with [ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([ 11 C]DASB; Wilson et al, 2000) have shown that 80% occupancy of SERT by SSRIs is needed for the improvement of depression symptom (Meyer et al, 2001(Meyer et al, , 2004Suhara et al, 2003). However, only one-third of patients show significant mood improvement in response to an initial antidepressant treatment (Trivedi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Yamamoto

Ohba

Nishiyama

et al. 2013

Neuropsychopharmacol

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Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys underwent four positron emission tomography measurements with [ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([ 11 C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ 11 C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT 1A -R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [ 11 C]DASB. No significant changes were observed in either 5-HT 1A -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased serotonin levels in the extracellular fluid of the prefrontal cortex. The present study demonstrates that subanesthetic ketamine selectively enhanced serotonergic transmission by inhibition of SERT activity. This action coexists with the rapid antidepressant effect of subanesthetic doses of ketamine. Further studies are needed to investigate whether the transient combination of SERT and NMDA reception inhibition enhances each other's antidepressant actions.

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“…Recent studies in baboons (Szabo et al, 2002) and humans (Frankle et al, 2004;Houle et al, 2000;Meyer et al, 2001;Wilson et al, 2000) have demonstrated the suitability of a new SERT ligand, [ 11 C]DASB, for studying serotonin neurons in the living brain. [ 11 C]DASB appears to have two critical advantages over [ 11 C]McN5652, including a greater specific-to-nonspecific equilibrium activity ratio, and a measurable plasma-free fraction for use in tracer modeling (Frankle et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB

McCann¹,

Szabó²,

Seckin³

et al. 2005

Neuropsychopharmacol

189

163

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(7)3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a widely used illicit drug that produces toxic effects on brain serotonin axons and axon terminals in animals. The results of clinical studies addressing MDMA's serotonin neurotoxic potential in humans have been inconclusive. In the present study, 23 abstinent MDMA users and 19 non-MDMA controls underwent quantitative positron emission tomography (PET) studies using [ 11 C]McN5652 and [ 11 C]DASB, first-and second-generation serotonin transporter (SERT) ligands previously validated in baboons for detecting MDMA-induced brain serotonin neurotoxicity. Global and regional distribution volumes (DVs) and two additional SERT-binding parameters (DV spec and DVR) were compared in the two subject populations using parametric statistical analyses. Data from PET studies revealed excellent correlations between the various binding parameters of [ 11 C] McN5652 and [ 11 C]DASB, both in individual brain regions and individual subjects. Global SERT reductions were found in MDMA users with both PET ligands, using all three of the above-mentioned SERT-binding parameters. Preplanned comparisons in 15 regions of interest demonstrated reductions in selected cortical and subcortical structures. Exploratory correlational analyses suggested that SERT measures recover with time, and that loss of the SERT is directly associated with MDMA use intensity. These quantitative PET data, obtained using validated first-and second-generation SERT PET ligands, provide strong evidence of reduced SERT density in some recreational MDMA users.

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Novel Radiotracers for Imaging the Serotonin Transporter by Positron Emission Tomography: Synthesis, Radiosynthesis, and in Vitro and ex Vivo Evaluation of ¹¹C-Labeled 2-(Phenylthio)araalkylamines

Cited by 227 publications

References 23 publications

Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB

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Novel Radiotracers for Imaging the Serotonin Transporter by Positron Emission Tomography: Synthesis, Radiosynthesis, and in Vitro and ex Vivo Evaluation of 11C-Labeled 2-(Phenylthio)araalkylamines

Cited by 227 publications

References 23 publications

Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB

Contact Info

Product

Resources

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Novel Radiotracers for Imaging the Serotonin Transporter by Positron Emission Tomography: Synthesis, Radiosynthesis, and in Vitro and ex Vivo Evaluation of ¹¹C-Labeled 2-(Phenylthio)araalkylamines