DASB

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Alan A Wilson - One of the best experts on this subject based on the ideXlab platform.

  • elevated serotonin transporter binding in depressed patients with parkinson s disease a preliminary pet study with 11c DASB
    Movement Disorders, 2008
    Co-Authors: Isabelle Boileau, Jerry J Warsh, Mark Guttman, Jean A Saintcyr, Tina Mccluskey, Pablo Rusjan, Sylvain Houle, Alan A Wilson, Jeffrey H Meyer
    Abstract:

    This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [11C]DASB. Depressed PD patients displayed a wide-spread increase (8–68%) in [11C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [11C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[11C]DASB findings in major depression, the present preliminary data suggest that increased [11C]DASB binding, possibly reflecting greater serotonin transporter density (up-regulation), might be a pathological feature of depression in Parkinson's disease—and possibly a characteristic of depressive illness in general. © 2008 Movement Disorder Society

  • serotonin transporter occupancy of high dose selective serotonin reuptake inhibitors during major depressive disorder measured with 11c DASB positron emission tomography
    Psychopharmacology, 2007
    Co-Authors: Aristotle N Voineskos, Pablo Rusjan, Sylvain Houle, Alan A Wilson, Nathalie Ginovart, Anahita Boovariwala, Sandra Sagrati, Stephen Sokolov, Edgar P Spencer, Jeffrey H Meyer
    Abstract:

    Previous work has shown 80% serotonin transporter (5-HTT) occupancy to be a consistent finding at the minimum therapeutic dose during selective serotonin reuptake inhibitor (SSRI) treatment. [11C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine positron emission tomography ([11C]DASB PET) is currently the best method available to quantify 5-HTT occupancy in humans. The purpose of the present study is to determine 5-HTT occupancy during high dose SSRI treatment using [11C]DASB PET. Twelve healthy subjects and 12 subjects with major depressive disorder completed the protocol. Depressed subjects received one [11C]DASB PET scan after a minimum of 4 weeks treatment at high doses of venlafaxine, sertraline, or citalopram. Baseline 5-HTT binding potential (BP) was taken as the average 5-HTT BP of the 12 healthy subjects. Mean striatal 5-HTT occupancy for each antidepressant group was approximately 85% at high therapeutic dose. This was significantly greater than 80% (one-sample t test; p < 0.04, venlafaxine group; p < 0.02, sertraline group; p < 0.01, citalopram group) for each high dose antidepressant group. Significantly greater 5-HTT blockade at high dose provides a rationale for raising the dose from the minimum therapeutic dose in specific clinical circumstances. It is likely that 15% unoccupied 5-HTT remains, which should be addressed in future drug development.

  • 11c ns 4194 versus 11c DASB for pet imaging of serotonin transporters in living porcine brain
    Synapse, 2003
    Co-Authors: Svend Borup Jensen, Alan A Wilson, Donald F Smith, Dirk Bender, Steen Jakobsen, Dan Peters, Elsebet Ostergaard Nielsen, Gunnar M Olsen, Jorgen Scheelkruger, Paul Cumming
    Abstract:

    In vitro, the novel diazabicyclononane NS 4194 has several thousandfold selectivity for blocking the transport into rat brain synaptosomes of [ 3 H]-serotonin in comparison to [3H]-dopamine or [ 3 H]-noradrenaline. We have prepared [ 1 1 C]-NS 4194 in order to test its properties for PET imaging of brain serotonin transporters in comparison with the well-documented tracer [ 1 1 C]-DASB. Both compounds had rapid clearance from blood to brain of living pigs. The apparent equilibrium distribution volumes in cerebellum were 35 ml g - 1 for [ 1 1 C]-NS 4194 and 11 ml g - 1 for [ 1 1 C]-DASB. Pretreatment of pigs with citalopram did not reduce the uptake of either tracer in cerebellum, validating the use of that tissue as a nonbinding reference tissue for kinetic analysis of specific binding. The binding potential (pB) calculated for [ 1 1 C]-NS 4194 using arterial input models was close to 0.5 in the telencephalon, and was 60% displaced by citalopram. However, the reference tissue method of Lammertsma was unsuited to calculate pB for this tracer, apparently due to its excessive nonspecific binding. In contrast to the relatively homogeneous binding of [ 1 1 C]-NS 4194, the pB of [ 1 1 C]-DASB ranged from 0.6 in frontal cortex to 2 in the mesencephalon when calculated by the method of Lammertsma. Parametric maps of the pB of [ 1 1 C]-DASB showed a pattern consistent with the known distribution of serotonin transporters in pig brain in vitro, and there was a uniform displacement of 80% of the specific binding after citalopram treatment in vivo. In conclusion, [ 1 1 C]-DASB is in several respects superior to [ 1 1 C]-NS 4194 for the detection of serotonin uptake sites by PET.

  • 11c DASB a tool for in vivo measurement of ssri induced occupancy of the serotonin transporter pet characterization and evaluation in cats
    Synapse, 2003
    Co-Authors: Nathalie Ginovart, Jeffrey H Meyer, Alan A Wilson, Doug Hussey, Sylvain Houle
    Abstract:

    The in vivo pharmacological profile of [(11)C]-DASB, a new radioligand developed for in vivo imaging of the serotonin transporter (SERT), was evaluated in the cat brain using positron emission tomography (PET). The in vivo distribution of [(11)C]-DASB binding was consistent with the known distribution of SERT sites in the cat brain in vitro with high uptakes of radioactivity in the midbrain and thalamus, intermediate levels in striatum, and modest to low levels of radioactivity in the neocortex and cerebellum, respectively. [(11)C]-DASB binding potential (BP) values ranged from about 0.2 in the neocortex to 2.2 in the midbrain. Radioligand binding in all brain regions except cerebellum was markedly reduced following pretreatment with fluoxetine and citalopram, but was unaffected by pretreatment with GBR12909, maprotiline, and haloperidol, indicating specificity of [(11)C]-DASB binding to the SERT. Two cats were each examined using PET and [(11)C]-DASB in a longitudinal fashion (from 30 min and up to 24 days) following a single i.v. dose of: 1) fluoxetine, and 2) citalopram at different dosages. Both drugs induced similar degrees of SERT occupancy at 30 min postinjection (approximately 90%). A comparison of citalopram and fluoxetine pharmacokinetics in the same animal and at the same dosage (1 mg/kg) showed that citalopram SERT occupancy and plasma half-lives were 9 times and 14 times shorter, respectively, than those of fluoxetine and norfluoxetine. In addition, studies performed after injection of the monoamine oxidase inhibitor tranylcypromine suggested that high levels of synaptic serotonin may compete with [(11)C]-DASB for binding on the SERT. These studies indicate that [(11)C]-DASB is a suitable PET radioligand for measuring drug occupancy of the SERT in vivo and has potential for monitoring in vivo changes in serotonin levels.

  • comparative evaluation in nonhuman primates of five pet radiotracers for imaging the serotonin transporters 11c mcn 5652 11c adam 11c DASB 11c dapa and 11c afm
    Journal of Cerebral Blood Flow and Metabolism, 2002
    Co-Authors: Yiyun Huang, Alan A Wilson, Dah Ren Hwang, Raj Narendran, Yasuhiko Sudo, Rano Chatterjee, Sung A Bae, Osama Mawlawi, Lawrence S Kegeles, Hank F Kung
    Abstract:

    The recent introduction of a number of new radiotracers suitable for imaging the serotonin transporters (SERT) has radically changed the field of SERT imaging. Whereas, until recently, only one selective SERT radiotracer was available ([11C]McN 5652) for SERT imaging with positron emission tomography (PET), several new C-11-labeled radiotracers of the -dimethyl-2-(arylthio)benzylamine class have been described as appropriate imaging agents for the SERT. The aim of this study was to conduct a comparative evaluation of four of the most promising agents in this class ([11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM) with the reference tracer [11C]McN 5652 under standardized experimental conditions. This evaluation included in vitro measurements of affinity and lipophilicity, and in vivo PET imaging experiments in baboons. In vitro, DASB displayed significantly lower affinity for SERT than the other four tracers. In the blood, [11C]DASB and [11C]AFM display faster clearance and higher free fractions. Brain uptake was analyzed with kinetic modeling using a one-tissue compartment model and the metabolite-corrected arterial input function. The kinetic uptake of [11C]DASB was significantly faster compared with the other compounds, and the scan duration required to derive time-independent estimates of regional distribution volumes was shorter. [11C]DAPA exhibited the slowest brain kinetic. Regional-specific-to-nonspecific equilibrium partition coefficient (V3") was the highest for [11C]AFM, followed by [11C]DASB and [11C]DAPA, which in turn provided higher V3" values than [11C]ADAM and [11C]McN 5652. From these experiments, two ligands emerged as superior radiotracers that provide a significant improvement over [11C]McN 5652 for PET imaging of SERT: [11C]DASB, because it enables the measurement of SERT availability in a shorter scanning time, and [11C]AFM, because its higher signal-to-noise ratios provide a more reliable measurement of SERT availability in brain regions with relatively low density of SERT, such as in the limbic system.

Robert B Innis - One of the best experts on this subject based on the ideXlab platform.

  • pet imaging of serotonin transporters with 11c DASB test retest reproducibility using a multilinear reference tissue parametric imaging method
    The Journal of Nuclear Medicine, 2006
    Co-Authors: Jae Seung Kim, Masanori Ichise, Janet Sangare, Robert B Innis
    Abstract:

    Parametric imaging of serotonin transporters (SERT) with 11C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([11C]DASB) PET is a useful data analysis tool. The purpose of this study was to evaluate the reproducibility of measurements of SERT binding potential (BP) and relative blood flow (R1) by a 2-parameter multilinear reference tissue parametric imaging method (MRTM2) for human [11C]DASB studies. Methods: Eight healthy subjects (3 men, 5 women; age, 26 ± 9 y) underwent 2 [11C]DASB PET scans separated by 1 h on the same day (dose, 703 ± 111 MBq). Parametric images of BP and R1 were generated by MRTM2 using the cerebellum as a reference region. The k′2 (clearance rate constant from the reference region) required by MRTM2 was estimated by the 3-parameter MRTM. Reproducibility of BP and R1 measurements was evaluated by calculating bias (100 × (retest – test/test), variability (SD of the bias), and reliability (intraclass correlation coefficient = ρ) for several representative regions of interest (ROIs). BP and R1 were estimated for ROI time–activity curves fitted by MRTM2 and were compared with those based on the parametric images. Results: The test–retest (0.066 ± 0.013/0.06 ± 0.011 min−1) MRTM k′2 reproducibility was excellent with small bias (3%) and variability (6%) and high reliability (0.95). Retest BP values were consistently lower than those of test BP values in all regions (a mean negative bias of ∼6%; P

  • biodistribution and radiation dosimetry of the serotonin transporter ligand 11c DASB determined from human whole body pet
    The Journal of Nuclear Medicine, 2004
    Co-Authors: Jianqiang Lu, Masanori Ichise, Jeih San Liow, Subroto Ghose, Doug Vines, Robert B Innis
    Abstract:

    11C-Labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) is a selective radioligand for the in vivo quantitation of serotonin transporters (SERTs) using PET. The goal of this study was to provide dosimetry estimates for "C-DASB based on human whole-body PET. Methods: Dynamic whole-body PET scans were acquired for 7 subjects after the injection of 669 ′ 97 MBq (18.1 ′ 2.6 mCi) of 1 1 C-DASB. The acquisition for each subject was obtained at 14 time points for a total of 115 min after injection of the radioligand. Regions of interest were placed over compressed planar images of source organs that could be visually identified to generate time-activity curves. Radiation burden to the body was calculated from residence times of these source organs using the MIRDOSE3.1 program. Results: The organs with. high radiation burden included the lungs, urinary bladder wall, kidneys, gallbladder wall, heart wall, spleen, and liver. The activity peaked within 10 min after the injection of 1 1 C-DASB for all these organs except two-the excretory organs gallbladder and urinary bladder wall, which had peak activities at 32 and 22 min, respectively. Mono-exponential fitting of activity overlying the urinary bladder suggested that approximately 12% of activity was excreted via the urine. Simulations in which the urinary voiding interval was decreased from 4.8 to 0.6 h produced only modest effects on the dose to the urinary bladder wall. With a 2.4-h voiding interval, the calculated effective dose was 6.98 μGy/MBq (25.8 mrem/mCi). Conclusion: The estimated radiation burden of 1 1 C-DASB is relatively modest and would allow multiple PET examinations of the same research subject per year.

  • pharmacological and genetic characterization of two selective serotonin transporter ligands 2 2 dimethylaminomethylphenylthio 5 fluoromethylphenylamine afm and 3 amino 4 2 dimethylaminomethyl phenylthio benzonitrile DASB
    Journal of Pharmacology and Experimental Therapeutics, 2004
    Co-Authors: Robert B Innis, Marc Laruelle, Masanori Ichise, Nicholas Seneca, Henry Huang, Dennis L Murphy
    Abstract:

    The expression and function of the serotonin transporter (SERT) is important in the regulation of mood and emotion. Determination of SERT alterations in physiological and pathological states is essential for understanding the role of SERT in mood regulation, and in the etiology and therapy of psychiatric disorders. Two SERT ligands, AFM ([ 3 H]2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine) and DASB ([ 3 H]3-amino-4-[2-(dimethylaminomethylphenylthio)]benzonitrile), have recently been developed for positron emission tomography (PET) imaging. The aim of the present study was to determine the selectivity of these compounds for SERT. Autoradiography of AFM or DASB binding was compared in the brains of mice with genetically normal, diminished, or absent SERT. In addition, the pharmacodynamic profile of [ 3 H]AFM was examined in the mouse brain. The distribution of [ 3 H]AFM and [ 3 H]DASB binding in the normal brains was consistent with that of previously studied serotonin reuptake inhibitors. Both ligands had negligible binding in the brain of SERT knockout mice, and binding was reduced approximately 50% in heterozygote SERT mice. The K d of [ 3 H]AFM binding in the cortex and midbrain was 1.6 and 1.0 nM, respectively. Competition studies showed that [ 3 H]AFM has very low affinity for norepinephrine and dopamine transporters as well as 5-HT receptors, including 5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 2C receptors. In addition, fenfluramine showed a low capability to compete with [ 3 H]AFM. The present results suggest that both AFM and DASB are highly selective SERT ligands potentially suitable for use in human PET studies of SERT.

  • radiation dosimetry estimates for the pet serotonin transporter probe 11c DASB determined from whole body imaging in non human primates
    Nuclear Medicine Communications, 2004
    Co-Authors: Dnyanesh Tipre, Jianqiang Lu, Masanori Ichise, Masahiro Fujita, Douglass Vines, Robert B Innis
    Abstract:

    The radiotracer 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile labelled in the N-methyl position (11C-DASB) is a selective radioligand for the in vivo quantification of serotonin transporters (SERTs) using positron emission tomography (PET). The current study quantified the distributi

  • radiation dosimetry estimates for the pet serotonin transporter probe 11c DASB determined from whole body imaging in non human primates
    Nuclear Medicine Communications, 2004
    Co-Authors: Dnyanesh Tipre, Masanori Ichise, Masahiro Fujita, Douglass Vines, Robert B Innis
    Abstract:

    The radiotracer 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile labelled in the N-methyl position (11C-DASB) is a selective radioligand for the in vivo quantification of serotonin transporters (SERTs) using positron emission tomography (PET). The current study quantified the distribution of activity in two rhesus monkeys after the injection of approximately 333 MBq (9 mCi) 11C-DASB. Whole-body images were acquired at 22 time points for a total of 120 min following injection of the radioligand. Source organs were identified at each time point from both tomographic images (using multiple regions of interest on each tomograph for each organ) and a single planar image (using a single region of interest for each organ). The peak activities in planar images in the five identified source organs (expressed as per cent injected dose (ID)) were lungs (24% ID at 1.5 min), kidneys (6.5% ID at 4 min), liver (8% ID at 3 min), brain (4% ID at 5 min) and spleen (0.42% ID at 3 min). Mono-exponential fitting of activity overlying the bladder suggested that approximately 14% of activity was excreted via the urine. The radiation burden to the body was calculated from residence times of these source organs and then scaled to corresponding human values. The calculated effective dose from tomographic and planar images was 6.0 and 6.4 microGy x MBq(-1) (22.3 and 23.7 mrad x mCi(-1)), respectively. The planar analysis was much easier to perform, and generally yielded slightly higher (i.e., more conservative) estimates of radiation burden than the tomographic analysis. The estimated radiation burden of 11C-DASB is relatively modest and would allow multiple scans per research subject per year.

Sylvain Houle - One of the best experts on this subject based on the ideXlab platform.

  • elevated serotonin transporter binding in depressed patients with parkinson s disease a preliminary pet study with 11c DASB
    Movement Disorders, 2008
    Co-Authors: Isabelle Boileau, Jerry J Warsh, Mark Guttman, Jean A Saintcyr, Tina Mccluskey, Pablo Rusjan, Sylvain Houle, Alan A Wilson, Jeffrey H Meyer
    Abstract:

    This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [11C]DASB. Depressed PD patients displayed a wide-spread increase (8–68%) in [11C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [11C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[11C]DASB findings in major depression, the present preliminary data suggest that increased [11C]DASB binding, possibly reflecting greater serotonin transporter density (up-regulation), might be a pathological feature of depression in Parkinson's disease—and possibly a characteristic of depressive illness in general. © 2008 Movement Disorder Society

  • serotonin transporter occupancy of high dose selective serotonin reuptake inhibitors during major depressive disorder measured with 11c DASB positron emission tomography
    Psychopharmacology, 2007
    Co-Authors: Aristotle N Voineskos, Pablo Rusjan, Sylvain Houle, Alan A Wilson, Nathalie Ginovart, Anahita Boovariwala, Sandra Sagrati, Stephen Sokolov, Edgar P Spencer, Jeffrey H Meyer
    Abstract:

    Previous work has shown 80% serotonin transporter (5-HTT) occupancy to be a consistent finding at the minimum therapeutic dose during selective serotonin reuptake inhibitor (SSRI) treatment. [11C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine positron emission tomography ([11C]DASB PET) is currently the best method available to quantify 5-HTT occupancy in humans. The purpose of the present study is to determine 5-HTT occupancy during high dose SSRI treatment using [11C]DASB PET. Twelve healthy subjects and 12 subjects with major depressive disorder completed the protocol. Depressed subjects received one [11C]DASB PET scan after a minimum of 4 weeks treatment at high doses of venlafaxine, sertraline, or citalopram. Baseline 5-HTT binding potential (BP) was taken as the average 5-HTT BP of the 12 healthy subjects. Mean striatal 5-HTT occupancy for each antidepressant group was approximately 85% at high therapeutic dose. This was significantly greater than 80% (one-sample t test; p < 0.04, venlafaxine group; p < 0.02, sertraline group; p < 0.01, citalopram group) for each high dose antidepressant group. Significantly greater 5-HTT blockade at high dose provides a rationale for raising the dose from the minimum therapeutic dose in specific clinical circumstances. It is likely that 15% unoccupied 5-HTT remains, which should be addressed in future drug development.

  • 11c DASB a tool for in vivo measurement of ssri induced occupancy of the serotonin transporter pet characterization and evaluation in cats
    Synapse, 2003
    Co-Authors: Nathalie Ginovart, Jeffrey H Meyer, Alan A Wilson, Doug Hussey, Sylvain Houle
    Abstract:

    The in vivo pharmacological profile of [(11)C]-DASB, a new radioligand developed for in vivo imaging of the serotonin transporter (SERT), was evaluated in the cat brain using positron emission tomography (PET). The in vivo distribution of [(11)C]-DASB binding was consistent with the known distribution of SERT sites in the cat brain in vitro with high uptakes of radioactivity in the midbrain and thalamus, intermediate levels in striatum, and modest to low levels of radioactivity in the neocortex and cerebellum, respectively. [(11)C]-DASB binding potential (BP) values ranged from about 0.2 in the neocortex to 2.2 in the midbrain. Radioligand binding in all brain regions except cerebellum was markedly reduced following pretreatment with fluoxetine and citalopram, but was unaffected by pretreatment with GBR12909, maprotiline, and haloperidol, indicating specificity of [(11)C]-DASB binding to the SERT. Two cats were each examined using PET and [(11)C]-DASB in a longitudinal fashion (from 30 min and up to 24 days) following a single i.v. dose of: 1) fluoxetine, and 2) citalopram at different dosages. Both drugs induced similar degrees of SERT occupancy at 30 min postinjection (approximately 90%). A comparison of citalopram and fluoxetine pharmacokinetics in the same animal and at the same dosage (1 mg/kg) showed that citalopram SERT occupancy and plasma half-lives were 9 times and 14 times shorter, respectively, than those of fluoxetine and norfluoxetine. In addition, studies performed after injection of the monoamine oxidase inhibitor tranylcypromine suggested that high levels of synaptic serotonin may compete with [(11)C]-DASB for binding on the SERT. These studies indicate that [(11)C]-DASB is a suitable PET radioligand for measuring drug occupancy of the SERT in vivo and has potential for monitoring in vivo changes in serotonin levels.

  • in vitro and in vivo characterisation of 11c DASB a probe for in vivo measurements of the serotonin transporter by positron emission tomography
    Nuclear Medicine and Biology, 2002
    Co-Authors: Alan A Wilson, Jeffrey H Meyer, Nathalie Ginovart, Doug Hussey, Sylvain Houle
    Abstract:

    Abstract 3-Amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, labeled with carbon-11 ([ 11 C]-DASB), is a recently introduced radiotracer for imaging the serotonin transporter (SERT) by positron emission tomography (PET). A series of in vitro and in vivo experiments were performed to further characterise the properties of [ 11 C]-DASB as an in vivo imaging agent for SERT. In vitro binding assays confirmed that DASB binds specifically to SERT with nanomolar affinity and high selectivity over a large number of other receptors, ion-channels and enzymes in the central nervous system. Ex vivo, [ 11 C]-DASB binding in rat brain was shown to be saturable (ED 50 of 56 nmoles/kg), and sensitive to both the number of available SERT binding sites and the number of viable serotonin neurons. Estimates of the radiation dose in man were extrapolated from rat biodistribution data (effective dose 5.5 E-03 mSv/MBq; critical organ -urinary bladder wall). Together with previous studies, the present findings indicate that [ 11 C]-DASB is a very useful radiopharmaceutical for probing changes in SERT densities using PET imaging in the living human brain.

  • positron emission tomography quantification of 11c DASB binding to the human serotonin transporter modeling strategies
    Journal of Cerebral Blood Flow and Metabolism, 2001
    Co-Authors: Nathalie Ginovart, Jeffrey H Meyer, Alan A Wilson, Doug Hussey, Sylvain Houle
    Abstract:

    [11C]-DASB, namely [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, is a new highly selective radioligand for the in vivo visualization of the serotonin transporter (SERT) using positron emission tomography (PET). The current study evaluates different kinetic modeling strategies for quantification of [11C]-DASB binding in five healthy humans. Kinetic analyses of tissue data were performed with a one-tissue (1CM) and a two-tissue (2CM) compartment model. Time-activity curves were well described by a 1CM for all regions. A 2CM model with four parameters failed to converge reliably. Reliable fits of the data were obtained only if no more than three parameters were allowed to vary. However, even then, the rate constants k3 and k4 were estimated with poor precision. Only the ratio k3/k4 was stable. Goodness of fit was not improved by using a 2CM as compared with a 1CM. The minimal study duration required to obtain stable k3/k4 estimates was 80 minutes. For routine use of [11C]-DASB, several...

Marc Laruelle - One of the best experts on this subject based on the ideXlab platform.

  • the 5 ht2a receptor and serotonin transporter in asperger s disorder a pet study with 11c mdl 100907 and 11c DASB
    Psychiatry Research-neuroimaging, 2011
    Co-Authors: Ragy R Girgis, Gordon W Frankle, Mark Slifstein, Anissa Abidargham, Marc Laruelle, Evdokia Anagnostou, Stacey Wasserman, Lauren Pepa, Alexander Kolevzon
    Abstract:

    Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [(11)C]MDL 100907 and [(11)C]DASB to characterize the 5-HT(2A) receptor and serotonin transporter in Asperger's Disorder. Seventeen individuals with Asperger's Disorder (age=34.3 ± 11.1 years) and 17 healthy controls (age=33.0 ± 9.6 years) were scanned with [(11)C]MDL 100907. Of the 17 patients, eight (age=29.7 ± 7.0 years) were also scanned with [¹¹C]DASB, as were eight healthy controls (age=28.7 ± 7.0 years). Patients with Asperger's Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by two-tissue compartment modeling. The primary outcome measure was regional binding potential BP(ND). Neither regional [¹¹C]MDL 100907 BP(ND) nor [¹¹C]DASB BP(ND) was statistically different between the Asperger's and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT(2A) receptors and serotonin transporters in adult subjects with Asperger's disorder.

  • estimation of serotonin transporter parameters with 11c DASB in healthy humans reproducibility and comparison of methods
    The Journal of Nuclear Medicine, 2006
    Co-Authors: Gordon W Frankle, Yiyun Huang, Dah Ren Hwang, Mark Slifstein, Anissa Abidargham, Rajesh Narendran, Roger N Gunn, Ashlie E Darr, Marc Laruelle
    Abstract:

    The aim of the present study was to define the optimal analytic method to derive accurate and reliable serotonin transporter (SERT) receptor parameters with 11C-3-amino-4-(2-[(dimethylamino)methyl]phenylthio)benzonitrile (11C-DASB). Methods: Nine healthy subjects (5 females, 4 males) underwent two 11C-DASB PET scans on the same day. Five analytic methods were used to estimate binding parameters in 10 brain regions: compartmental modeling with 1- and 2-tissue compartment models (1TC and 2TC), data-driven estimation of parametric images based on compartmental theory (DEPICT) analysis, graphical analysis, and the simplified reference tissue model (SRTM). Two variations in the fitting procedure of the SRTM method were evaluated: nonlinear optimization and basis function approach. The test/retest variability (VAR) and intraclass correlation coefficient (ICC or reliability) were assessed for 3 outcome measures: distribution volume (VT), binding potential (BP), and specific to nonspecific equilibrium partition coefficient (V3″). Results: All methods gave similar values across all regions. The variability of VT was excellent (≤10%) in all regions, for the 1TC, 2TC, DEPICT, and graphical approaches. The variability of BP and V3″ was good in regions of high SERT density and poorer in regions of moderate and lower densities. The ICC of all 3 outcome measures was excellent in all regions. The basis function implementation of SRTM demonstrated improved reliability compared with nonlinear optimization, particularly in moderate and low-binding regions. Conclusion: The results of this study indicate that 11C-DASB can be used to measure SERT parameters with high reliability and low variability in receptor-rich regions of the brain, with somewhat less reliability and increased variability in regions of moderate SERT density and poor reproducibility in low-density regions.

  • serotonin transporter availability in patients with schizophrenia a positron emission tomography imaging study with 11c DASB
    Biological Psychiatry, 2005
    Co-Authors: Gordon W Frankle, Yiyun Huang, Dah Ren Hwang, Marc Laruelle, Rajesh Narendran, Ilise Lombardo, Claudine Cangiano, Roberto Gil, Anissa Abidargham
    Abstract:

    Background Postmortem studies have reported several alterations in serotonin transporter (SERT) binding parameters in patients with schizophrenia. The aim of this study was to compare SERT availability in vivo in patients with schizophrenia and matched control subjects. Methods Ten medication-free patients with schizophrenia and 10 healthy subjects underwent positron emission tomography (PET) scans for 90 min after 11 C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([ 11 C]DASB) injection. Metabolite-corrected arterial input function was measured. Regional distribution volumes (mL/g) were derived with a two tissue compartment kinetic model. Outcome measures for SERT availability included binding potential (BP) and the specific-to-nonspecific equilibrium partition coefficient (V 3 ″). Ten brain regions with high density of SERT and where SERT availability can be reliably quantified with [ 11 C]DASB were included in the analysis. Results No significant differences were observed in regional BP or V 3 ″ between patients and control subjects. No significant relationships were observed between regional SERT availability and severity of positive, negative, and depressive symptoms. Conclusions This study failed to detect alterations of SERT availability in patients with schizophrenia; however, this study does not rule out the possibility that schizophrenia might be associated with alterations of SERT density in the cortical regions, where the [ 11 C]DASB-specific binding signal is too low for reliable quantification of SERT.

  • effects of reduced endogenous 5 ht on the in vivo binding of the serotonin transporter radioligand 11c DASB in healthy humans
    Synapse, 2005
    Co-Authors: Peter S Talbot, Gordon W Frankle, Yiyun Huang, Dah Ren Hwang, Mark Slifstein, Anissa Abidargham, Raymond F Suckow, Marc Laruelle
    Abstract:

    Although abnormal serotonin (5-HT) function is implicated in a range of mental disorders, there is currently no method to directly assess 5-HT synaptic levels in the living human brain. The in vivo binding of some dopamine (DA) radioligands such as (11)C-raclopride is affected by fluctuations in endogenous DA, thus providing an indirect measure of DA presynaptic activity. Attempts to identify a serotonergic radiotracer with similar properties have proved unsuccessful. Here, we investigated in humans the effects of reduced synaptic 5-HT on the in vivo binding of the 5-HT transporter (SERT) radioligand (11)C-DASB, using Positron Emission Tomography (PET) and the rapid tryptophan depletion (RTD) technique. Eight (8) subjects (5M, 3F) were scanned with (11)C-DASB under control and reduced endogenous 5-HT conditions, in a within-subject, double-blind, counterbalanced, crossover design. Regional distribution volumes (V(T)) were calculated using kinetic modeling and metabolite-corrected arterial input function. (11)C-DASB specific binding was estimated as binding potential (BP) and specific to nonspecific equilibrium partition coefficient (V(")(3)), using the cerebellum as reference region. RTD caused small but significant mean reductions in (11)C-DASB V(T) (-6.1%) and BP (-4.5%) across brain regions, probably explained by a concomitant reduction in (11)C-DASB plasma free fraction (f(1)) of similar magnitude. No significant change in (11)C-DASB V(")(3) was observed between control and reduced 5-HT conditions. Nor was there a significant relationship between the magnitude of tryptophan depletion and change in BP and V(")(3) across individual subjects. These results suggest that (11)C-DASB in vivo binding is not affected by reductions in endogenous 5-HT.

  • comparative evaluation of serotonin transporter radioligands 11c DASB and 11c mcn 5652 in healthy humans
    The Journal of Nuclear Medicine, 2004
    Co-Authors: Gordon W Frankle, Ronald L Van Heertum, Yiyun Huang, Dah Ren Hwang, Peter S Talbot, Mark Slifstein, Anissa Abidargham, Marc Laruelle
    Abstract:

    Alterations of serotonin transporters (SERT) are implicated in a large number of psychiatric conditions. 11C-(+)-6β-(4-Methylthiophenyl)-1,2,3,5,6α,10β-hexahydropyrrolo[2,1-a]isoquinoline (11C-McN 5652) was the first PET radiotracer successfully developed as a SERT imaging agent. Recently, 11C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile (11C-DASB) was introduced as an alternative to 11C-McN 5652. Comparative evaluation of 11C-DASB and 11C-McN 5652 in baboons indicates that 11C-DASB is associated with (a) lower nonspecific binding in the brain, (b) higher plasma free fraction, and (c) faster plasma clearance and brain uptake kinetics, enabling measurement of SERT parameters in a shorter scanning time. The purpose of this study was to compare these 2 agents in healthy humans. Methods: Six healthy volunteers underwent 2 PET scans on the same day, one with 11C-DASB and one with 11C-McN 5652, in counterbalanced order. Regional distribution volumes (VT) were derived for 16 brain regions by kinetic analysis using the arterial input function. Results: Both 11C-DASB and 11C-McN 5652 displayed similar patterns of accumulation: highest levels in the midbrain, thalamus and striatum; intermediate in the limbic regions; low in the neocortex; and lowest in the cerebellum. 11C-DASB cerebellar VT (10.1 ± 2.0 mL g−1) was lower than that of 11C-McN 5652 (20.8 ± 3.6 mL g−1), indicating lower nonspecific binding. As a result, regional specific-to-nonspecific equilibrium partition coefficients (V3″) of 11C-DASB were higher compared with those of 11C-McN 5652 (for example, midbrain V3″ of 11C-DASB and 11C-McN 5652 were 2.04 ± 0.44 and 1.20 ± 0.34, respectively). The plasma free fraction was 8.9% ± 1.6% for 11C-DASB and was not measurable for 11C-McN 5652. In contrast to the situation observed in baboons, plasma clearances of both compounds were similar in humans, and the minimal scanning times required to derive time-invariant distribution volumes in all regions were comparable for both tracers (95 min). Conclusion: With the exception of the scanning time, predictions from baboon studies were confirmed in humans. The higher specific-to-nonspecific ratios of 11C-DASB are a critical advantage. This property will be especially important for the measurement of SERT in regions with moderate density, such as the limbic regions, where alterations of serotonin transmission might be associated with anxiety and depression.

Masanori Ichise - One of the best experts on this subject based on the ideXlab platform.

  • reduced serotonin transporter binding in the insular cortex in patients with obsessive compulsive disorder a 11c DASB pet study
    NeuroImage, 2010
    Co-Authors: Masanori Ichise, Ryohei Matsumoto, Hiroshi Ito, Tomomichi Ando, Hidehiko Takahashi, Yoko Ikoma, Jun Kosaka
    Abstract:

    The serotonin transporter (5-HTT) and other markers of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [(123)I]beta-CIT or positron emission tomography (PET) with [(11)C]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [(11)C]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [(11)C]DASB. The severity of OCD was assessed by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (mean+/-SD: 22+/-7.6, range: 7-32). The binding potential (BP(ND)) of [(11)C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BP(ND) were analyzed using a statistical parametric mapping system. Significant reductions of BP(ND) were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BP(ND) in the insular cortex. Although significantly reduced BP(ND) in the orbitofrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BP(ND). The change in [(11)C]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD.

  • pet imaging of serotonin transporters with 11c DASB test retest reproducibility using a multilinear reference tissue parametric imaging method
    The Journal of Nuclear Medicine, 2006
    Co-Authors: Jae Seung Kim, Masanori Ichise, Janet Sangare, Robert B Innis
    Abstract:

    Parametric imaging of serotonin transporters (SERT) with 11C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([11C]DASB) PET is a useful data analysis tool. The purpose of this study was to evaluate the reproducibility of measurements of SERT binding potential (BP) and relative blood flow (R1) by a 2-parameter multilinear reference tissue parametric imaging method (MRTM2) for human [11C]DASB studies. Methods: Eight healthy subjects (3 men, 5 women; age, 26 ± 9 y) underwent 2 [11C]DASB PET scans separated by 1 h on the same day (dose, 703 ± 111 MBq). Parametric images of BP and R1 were generated by MRTM2 using the cerebellum as a reference region. The k′2 (clearance rate constant from the reference region) required by MRTM2 was estimated by the 3-parameter MRTM. Reproducibility of BP and R1 measurements was evaluated by calculating bias (100 × (retest – test/test), variability (SD of the bias), and reliability (intraclass correlation coefficient = ρ) for several representative regions of interest (ROIs). BP and R1 were estimated for ROI time–activity curves fitted by MRTM2 and were compared with those based on the parametric images. Results: The test–retest (0.066 ± 0.013/0.06 ± 0.011 min−1) MRTM k′2 reproducibility was excellent with small bias (3%) and variability (6%) and high reliability (0.95). Retest BP values were consistently lower than those of test BP values in all regions (a mean negative bias of ∼6%; P

  • biodistribution and radiation dosimetry of the serotonin transporter ligand 11c DASB determined from human whole body pet
    The Journal of Nuclear Medicine, 2004
    Co-Authors: Jianqiang Lu, Masanori Ichise, Jeih San Liow, Subroto Ghose, Doug Vines, Robert B Innis
    Abstract:

    11C-Labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) is a selective radioligand for the in vivo quantitation of serotonin transporters (SERTs) using PET. The goal of this study was to provide dosimetry estimates for "C-DASB based on human whole-body PET. Methods: Dynamic whole-body PET scans were acquired for 7 subjects after the injection of 669 ′ 97 MBq (18.1 ′ 2.6 mCi) of 1 1 C-DASB. The acquisition for each subject was obtained at 14 time points for a total of 115 min after injection of the radioligand. Regions of interest were placed over compressed planar images of source organs that could be visually identified to generate time-activity curves. Radiation burden to the body was calculated from residence times of these source organs using the MIRDOSE3.1 program. Results: The organs with. high radiation burden included the lungs, urinary bladder wall, kidneys, gallbladder wall, heart wall, spleen, and liver. The activity peaked within 10 min after the injection of 1 1 C-DASB for all these organs except two-the excretory organs gallbladder and urinary bladder wall, which had peak activities at 32 and 22 min, respectively. Mono-exponential fitting of activity overlying the urinary bladder suggested that approximately 12% of activity was excreted via the urine. Simulations in which the urinary voiding interval was decreased from 4.8 to 0.6 h produced only modest effects on the dose to the urinary bladder wall. With a 2.4-h voiding interval, the calculated effective dose was 6.98 μGy/MBq (25.8 mrem/mCi). Conclusion: The estimated radiation burden of 1 1 C-DASB is relatively modest and would allow multiple PET examinations of the same research subject per year.

  • pharmacological and genetic characterization of two selective serotonin transporter ligands 2 2 dimethylaminomethylphenylthio 5 fluoromethylphenylamine afm and 3 amino 4 2 dimethylaminomethyl phenylthio benzonitrile DASB
    Journal of Pharmacology and Experimental Therapeutics, 2004
    Co-Authors: Robert B Innis, Marc Laruelle, Masanori Ichise, Nicholas Seneca, Henry Huang, Dennis L Murphy
    Abstract:

    The expression and function of the serotonin transporter (SERT) is important in the regulation of mood and emotion. Determination of SERT alterations in physiological and pathological states is essential for understanding the role of SERT in mood regulation, and in the etiology and therapy of psychiatric disorders. Two SERT ligands, AFM ([ 3 H]2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine) and DASB ([ 3 H]3-amino-4-[2-(dimethylaminomethylphenylthio)]benzonitrile), have recently been developed for positron emission tomography (PET) imaging. The aim of the present study was to determine the selectivity of these compounds for SERT. Autoradiography of AFM or DASB binding was compared in the brains of mice with genetically normal, diminished, or absent SERT. In addition, the pharmacodynamic profile of [ 3 H]AFM was examined in the mouse brain. The distribution of [ 3 H]AFM and [ 3 H]DASB binding in the normal brains was consistent with that of previously studied serotonin reuptake inhibitors. Both ligands had negligible binding in the brain of SERT knockout mice, and binding was reduced approximately 50% in heterozygote SERT mice. The K d of [ 3 H]AFM binding in the cortex and midbrain was 1.6 and 1.0 nM, respectively. Competition studies showed that [ 3 H]AFM has very low affinity for norepinephrine and dopamine transporters as well as 5-HT receptors, including 5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 2C receptors. In addition, fenfluramine showed a low capability to compete with [ 3 H]AFM. The present results suggest that both AFM and DASB are highly selective SERT ligands potentially suitable for use in human PET studies of SERT.

  • radiation dosimetry estimates for the pet serotonin transporter probe 11c DASB determined from whole body imaging in non human primates
    Nuclear Medicine Communications, 2004
    Co-Authors: Dnyanesh Tipre, Jianqiang Lu, Masanori Ichise, Masahiro Fujita, Douglass Vines, Robert B Innis
    Abstract:

    The radiotracer 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile labelled in the N-methyl position (11C-DASB) is a selective radioligand for the in vivo quantification of serotonin transporters (SERTs) using positron emission tomography (PET). The current study quantified the distributi

Related terms

DASB - 15 days free trial to Access Experts & Abstracts