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George A. Ricaurte - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Detection of Short- and Long-Term MDMA Neurotoxicity—A Positron Emission Tomography Study in the Living Baboon Brain
2013Co-Authors: Ursula Scheffel, Zsolt Szabo, William B. Mathews, Paige A. Finley, Robert F. Dannals, Hayden T. Ravert, Katalina Szabo, Jie Yuan, George A. RicaurteAbstract:ABSTRACT The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [ 11C](�)McN 5652, a potent 5-HT transporter ligand, as well as [ 11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [ 11C](�)McN5652, [ 11C](�)McN5652 (the inactive enantiomer of the active enantiomer [ 11C](�)McN5652) and [ 11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [ 11C](�)McN 5652, but not with [ 11C](�)McN5652 or [ 11C]RTI-55. Reductions in specific [ 11C](�)McN5652 binding (calculated as the difference in radioactivity concentrations between (�) and (�) [ 11C]McN5652) ranged from 44 % in the pons to 89 % in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measure
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quantitative positron emission tomography studies of the serotonin transporter in humans previously treated with the appetite suppressants fenfluramine or dexfenfluramine
Molecular Imaging and Biology, 2007Co-Authors: Una D Mccann, Zsolt Szabo, Robert F. Dannals, Melin Vranesic, Esen Seckin, Gary S Wand, Anna Duval, George A. RicaurteAbstract:Purpose The appetite suppressants fenfluramine and dexfenfluramine were widely prescribed before being withdrawn from the market in 1997. Both drugs are known to have the potential to damage brain serotonin (5-HT) axons and axon terminals in animals, including nonhuman primates. This study used quantitative positron emission tomography (PET) with [11C] McN5652, a serotonin transporter (SERT) ligand to determine whether humans previously exposed to fenfluramines showed reductions in SERT binding parameters.
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quantitative pet studies of the serotonin transporter in mdma users and controls using 11c McN5652 and 11c dasb
Neuropsychopharmacology, 2005Co-Authors: Una D Mccann, Zsolt Szabo, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Esen Seckin, P L Rosenblatt, George A. RicaurteAbstract:(±)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 [11C]McN5652 and [11C]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 (DVspec 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 [11C] McN5652 and [11C]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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comparison of 11c McN5652 and 11c dasb as serotonin transporter radioligands under various experimental conditions
The Journal of Nuclear Medicine, 2002Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Alan A Wilson, Una D Mccann, Taofeek K Owonikoko, John Hilton, George A. RicaurteAbstract:The brain serotonin (5-HT) system has been implicated in several neuropsychiatric conditions, including major depression, anxiety, obsessive compulsive disorder, and schizophrenia. Because of the perceived importance of the brain 5-HT system in these diseases, as well as a variety of normal brain functions (e.g., appetite, sleep), there has been considerable interest in developing neuroimaging techniques that permit assessment of 5-HT neurons in the living human brain. To this end, several research teams have developed and evaluated various SPECT and PET radiotracers for measurements of various components of the brain 5-HT system (1-6). With regard to PET, a series of radioligands showing high binding to the 5-HT transporter (SERT) in vitro have been evaluated, but most have been found to have insufficient specificity or selectivity for the SERT in vivo (7). To date, one of the more promising PET SERT radioligands identified is trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-11C-McN5652). (+)-11C-McN5652 binds selectively to the SERT, and its regional distribution of binding in humans correlates well with the known distribution of the SERT in human brain (8-10). In addition, studies in baboons and humans exposed to the brain 5-HT neurotoxin, (±)-3,4-methylenedioxymethamphetamine (MDMA), show significant reductions in (+)-11C-McN5652 binding (11-13). However, usefulness of (+)-11C-McN5652 may be limited by its nonspecific binding and slow release from specific binding sites (14,15). There have been recent reports that an alternative SERT radioligand,3-11C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (11C-DASB), holds promise for use as a SERT PET ligand (16,17). Preclinical studies indicate that, like (+)-11C-McN5652, 11C-DASB has high affinity and selectivity for the SERT in vitro and that, in vivo, it shows saturable and selective binding to the SERT in rodents. Also, damage of 5-HT axon terminals with the neurotoxin p-chloroamphetamine is associated with significant reductions in 11C-DASB binding in vivo in rodents, and low concentrations of radioactive metabolites in rat brain relative to the parent compound (17) suggest that this radioligand holds significant potential for use in evaluating the status of the brain SERT in humans. Notably, initial PET studies in humans (18) indicate that 11C-DASB has highly suitable characteristics for evaluating the status of the SERT in clinical settings and that 11C-DASB can successfully detect SERT occupancy by paroxetine and citalopram (19). The purpose of this study was to compare (+)-11C-McN5652 and 11C-DASB as PET ligands of the SERT in nonhuman primates. In particular, we sought to (a) compare binding characteristics of both radioligands to the SERT in a saline-treated baboon (normal SERT density), (b) compare the ability of the 2 radioligands to detect reductions in SERT density induced by the selective 5-HT neurotoxin MDMA, (c) evaluate the capability of both ligands to detect reduced SERT availability after pretreatment with paroxetine, and (d) determine how binding parameters of the 2 radioligands correlate with direct measures of brain 5-HT axonal markers measured ex vivo.
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kinetic analysis of 11c McN5652 a serotonin transporter radioligand
Journal of Cerebral Blood Flow and Metabolism, 1999Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Hayden T. Ravert, Katalina Szabo, George A. Ricaurte, Michael A Kraut, Sally C Palmon, Robert F. DannalsAbstract:The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)-McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](–)-McN5652. The impulse response function was calculated by deconvolution analysis of regional time–activity curves, and its peak value (fmax), its retention value at 75 minutes (fT), and its normalized retention (frel = fT/fmax) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DVT) and its specific binding component (DVs). Both the noncompartmental (fT, frel) and the compartmental parameters (DV) were investigated with and without...
Zsolt Szabo - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Detection of Short- and Long-Term MDMA Neurotoxicity—A Positron Emission Tomography Study in the Living Baboon Brain
2013Co-Authors: Ursula Scheffel, Zsolt Szabo, William B. Mathews, Paige A. Finley, Robert F. Dannals, Hayden T. Ravert, Katalina Szabo, Jie Yuan, George A. RicaurteAbstract:ABSTRACT The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [ 11C](�)McN 5652, a potent 5-HT transporter ligand, as well as [ 11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [ 11C](�)McN5652, [ 11C](�)McN5652 (the inactive enantiomer of the active enantiomer [ 11C](�)McN5652) and [ 11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [ 11C](�)McN 5652, but not with [ 11C](�)McN5652 or [ 11C]RTI-55. Reductions in specific [ 11C](�)McN5652 binding (calculated as the difference in radioactivity concentrations between (�) and (�) [ 11C]McN5652) ranged from 44 % in the pons to 89 % in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measure
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quantitative positron emission tomography studies of the serotonin transporter in humans previously treated with the appetite suppressants fenfluramine or dexfenfluramine
Molecular Imaging and Biology, 2007Co-Authors: Una D Mccann, Zsolt Szabo, Robert F. Dannals, Melin Vranesic, Esen Seckin, Gary S Wand, Anna Duval, George A. RicaurteAbstract:Purpose The appetite suppressants fenfluramine and dexfenfluramine were widely prescribed before being withdrawn from the market in 1997. Both drugs are known to have the potential to damage brain serotonin (5-HT) axons and axon terminals in animals, including nonhuman primates. This study used quantitative positron emission tomography (PET) with [11C] McN5652, a serotonin transporter (SERT) ligand to determine whether humans previously exposed to fenfluramines showed reductions in SERT binding parameters.
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quantitative pet studies of the serotonin transporter in mdma users and controls using 11c McN5652 and 11c dasb
Neuropsychopharmacology, 2005Co-Authors: Una D Mccann, Zsolt Szabo, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Esen Seckin, P L Rosenblatt, George A. RicaurteAbstract:(±)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 [11C]McN5652 and [11C]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 (DVspec 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 [11C] McN5652 and [11C]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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comparison of 11c McN5652 and 11c dasb as serotonin transporter radioligands under various experimental conditions
The Journal of Nuclear Medicine, 2002Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Alan A Wilson, Una D Mccann, Taofeek K Owonikoko, John Hilton, George A. RicaurteAbstract:The brain serotonin (5-HT) system has been implicated in several neuropsychiatric conditions, including major depression, anxiety, obsessive compulsive disorder, and schizophrenia. Because of the perceived importance of the brain 5-HT system in these diseases, as well as a variety of normal brain functions (e.g., appetite, sleep), there has been considerable interest in developing neuroimaging techniques that permit assessment of 5-HT neurons in the living human brain. To this end, several research teams have developed and evaluated various SPECT and PET radiotracers for measurements of various components of the brain 5-HT system (1-6). With regard to PET, a series of radioligands showing high binding to the 5-HT transporter (SERT) in vitro have been evaluated, but most have been found to have insufficient specificity or selectivity for the SERT in vivo (7). To date, one of the more promising PET SERT radioligands identified is trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-11C-McN5652). (+)-11C-McN5652 binds selectively to the SERT, and its regional distribution of binding in humans correlates well with the known distribution of the SERT in human brain (8-10). In addition, studies in baboons and humans exposed to the brain 5-HT neurotoxin, (±)-3,4-methylenedioxymethamphetamine (MDMA), show significant reductions in (+)-11C-McN5652 binding (11-13). However, usefulness of (+)-11C-McN5652 may be limited by its nonspecific binding and slow release from specific binding sites (14,15). There have been recent reports that an alternative SERT radioligand,3-11C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (11C-DASB), holds promise for use as a SERT PET ligand (16,17). Preclinical studies indicate that, like (+)-11C-McN5652, 11C-DASB has high affinity and selectivity for the SERT in vitro and that, in vivo, it shows saturable and selective binding to the SERT in rodents. Also, damage of 5-HT axon terminals with the neurotoxin p-chloroamphetamine is associated with significant reductions in 11C-DASB binding in vivo in rodents, and low concentrations of radioactive metabolites in rat brain relative to the parent compound (17) suggest that this radioligand holds significant potential for use in evaluating the status of the brain SERT in humans. Notably, initial PET studies in humans (18) indicate that 11C-DASB has highly suitable characteristics for evaluating the status of the SERT in clinical settings and that 11C-DASB can successfully detect SERT occupancy by paroxetine and citalopram (19). The purpose of this study was to compare (+)-11C-McN5652 and 11C-DASB as PET ligands of the SERT in nonhuman primates. In particular, we sought to (a) compare binding characteristics of both radioligands to the SERT in a saline-treated baboon (normal SERT density), (b) compare the ability of the 2 radioligands to detect reductions in SERT density induced by the selective 5-HT neurotoxin MDMA, (c) evaluate the capability of both ligands to detect reduced SERT availability after pretreatment with paroxetine, and (d) determine how binding parameters of the 2 radioligands correlate with direct measures of brain 5-HT axonal markers measured ex vivo.
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kinetic analysis of 11c McN5652 a serotonin transporter radioligand
Journal of Cerebral Blood Flow and Metabolism, 1999Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Hayden T. Ravert, Katalina Szabo, George A. Ricaurte, Michael A Kraut, Sally C Palmon, Robert F. DannalsAbstract:The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)-McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](–)-McN5652. The impulse response function was calculated by deconvolution analysis of regional time–activity curves, and its peak value (fmax), its retention value at 75 minutes (fT), and its normalized retention (frel = fT/fmax) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DVT) and its specific binding component (DVs). Both the noncompartmental (fT, frel) and the compartmental parameters (DV) were investigated with and without...
Ursula Scheffel - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Detection of Short- and Long-Term MDMA Neurotoxicity—A Positron Emission Tomography Study in the Living Baboon Brain
2013Co-Authors: Ursula Scheffel, Zsolt Szabo, William B. Mathews, Paige A. Finley, Robert F. Dannals, Hayden T. Ravert, Katalina Szabo, Jie Yuan, George A. RicaurteAbstract:ABSTRACT The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [ 11C](�)McN 5652, a potent 5-HT transporter ligand, as well as [ 11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [ 11C](�)McN5652, [ 11C](�)McN5652 (the inactive enantiomer of the active enantiomer [ 11C](�)McN5652) and [ 11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [ 11C](�)McN 5652, but not with [ 11C](�)McN5652 or [ 11C]RTI-55. Reductions in specific [ 11C](�)McN5652 binding (calculated as the difference in radioactivity concentrations between (�) and (�) [ 11C]McN5652) ranged from 44 % in the pons to 89 % in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measure
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comparison of 11c McN5652 and 11c dasb as serotonin transporter radioligands under various experimental conditions
The Journal of Nuclear Medicine, 2002Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Alan A Wilson, Una D Mccann, Taofeek K Owonikoko, John Hilton, George A. RicaurteAbstract:The brain serotonin (5-HT) system has been implicated in several neuropsychiatric conditions, including major depression, anxiety, obsessive compulsive disorder, and schizophrenia. Because of the perceived importance of the brain 5-HT system in these diseases, as well as a variety of normal brain functions (e.g., appetite, sleep), there has been considerable interest in developing neuroimaging techniques that permit assessment of 5-HT neurons in the living human brain. To this end, several research teams have developed and evaluated various SPECT and PET radiotracers for measurements of various components of the brain 5-HT system (1-6). With regard to PET, a series of radioligands showing high binding to the 5-HT transporter (SERT) in vitro have been evaluated, but most have been found to have insufficient specificity or selectivity for the SERT in vivo (7). To date, one of the more promising PET SERT radioligands identified is trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-11C-McN5652). (+)-11C-McN5652 binds selectively to the SERT, and its regional distribution of binding in humans correlates well with the known distribution of the SERT in human brain (8-10). In addition, studies in baboons and humans exposed to the brain 5-HT neurotoxin, (±)-3,4-methylenedioxymethamphetamine (MDMA), show significant reductions in (+)-11C-McN5652 binding (11-13). However, usefulness of (+)-11C-McN5652 may be limited by its nonspecific binding and slow release from specific binding sites (14,15). There have been recent reports that an alternative SERT radioligand,3-11C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (11C-DASB), holds promise for use as a SERT PET ligand (16,17). Preclinical studies indicate that, like (+)-11C-McN5652, 11C-DASB has high affinity and selectivity for the SERT in vitro and that, in vivo, it shows saturable and selective binding to the SERT in rodents. Also, damage of 5-HT axon terminals with the neurotoxin p-chloroamphetamine is associated with significant reductions in 11C-DASB binding in vivo in rodents, and low concentrations of radioactive metabolites in rat brain relative to the parent compound (17) suggest that this radioligand holds significant potential for use in evaluating the status of the brain SERT in humans. Notably, initial PET studies in humans (18) indicate that 11C-DASB has highly suitable characteristics for evaluating the status of the SERT in clinical settings and that 11C-DASB can successfully detect SERT occupancy by paroxetine and citalopram (19). The purpose of this study was to compare (+)-11C-McN5652 and 11C-DASB as PET ligands of the SERT in nonhuman primates. In particular, we sought to (a) compare binding characteristics of both radioligands to the SERT in a saline-treated baboon (normal SERT density), (b) compare the ability of the 2 radioligands to detect reductions in SERT density induced by the selective 5-HT neurotoxin MDMA, (c) evaluate the capability of both ligands to detect reduced SERT availability after pretreatment with paroxetine, and (d) determine how binding parameters of the 2 radioligands correlate with direct measures of brain 5-HT axonal markers measured ex vivo.
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kinetic analysis of 11c McN5652 a serotonin transporter radioligand
Journal of Cerebral Blood Flow and Metabolism, 1999Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Hayden T. Ravert, Katalina Szabo, George A. Ricaurte, Michael A Kraut, Sally C Palmon, Robert F. DannalsAbstract:The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)-McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](–)-McN5652. The impulse response function was calculated by deconvolution analysis of regional time–activity curves, and its peak value (fmax), its retention value at 75 minutes (fT), and its normalized retention (frel = fT/fmax) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DVT) and its specific binding component (DVs). Both the noncompartmental (fT, frel) and the compartmental parameters (DV) were investigated with and without...
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in vivo detection of short and long term mdma neurotoxicity a positron emission tomography study in the living baboon brain
Synapse, 1998Co-Authors: Ursula Scheffel, Zsolt Szabo, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Katalina Szabo, Jie Yuan, Paige Finley, George A. RicaurteAbstract:The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [11C](+)McN 5652, a potent 5-HT transporter ligand, as well as [11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [11C](+)McN5652, [11C](−)McN5652 (the inactive enantiomer of the active enantiomer [11C](+)McN5652) and [11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [11C](+)McN 5652, but not with [11C](−)McN5652 or [11C]RTI-55. Reductions in specific [11C](+)McN5652 binding (calculated as the difference in radioactivity concentrations between (+) and (−)[11C]McN5652) ranged from 44% in the pons to 89% in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measured after sacrifice of the animal. The results of these studies indicate that PET imaging of the living nonhuman primate brain with [11C](+)McN 5652 can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity. Using PET, it should also be feasible to use [11C](+)McN5652 to determine whether human MDMA users are also susceptible to MDMA's neurotoxic effects. Synapse 29:183–192, 1998. © 1998 Wiley-Liss, Inc.
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positron emission tomography of 5 ht reuptake sites in the human brain with c 11 McN5652 extraction of characteristic images by artificial neural network analysis
Behavioural Brain Research, 1995Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Hayden T. Ravert, Pan Fu Kao, John L Musachio, Robert F. DannalsAbstract:Abstract The goal of this work was to identify the distribution of serotonin transporters in the human brain with [ 11 C](+)McN5652/PET. Four healthy volunteers were studied. To determine non-specific binding, a PET study was also performed with the inactive enantiomer [ 11 C](−)McN5652 as well as with [ 11 C](+)McN5652 after pretreatment with fluoxetine. For pattern extraction the PET data sets were analyzed by a back-propagation neural network. Two pharmacokinetic patterns and two characteristic images were separated; one representing specific binding, the other representing non-specific binding. The specific binding image showed characteristic distribution of serotonin transporters with [ 11 C](+)McN5652. The pattern images demonstrated an improvement in image quality compared to the original PET images (reduced variance, higher region-to-cerebellum ratio, good correlation with known density of serotonin transporters). The non-specific binding images extracted from [ 11 C](−)McN5652/PET were similar to those of [ 11 C](−)McN5652 and [ 11 C](−)McN5652 with fluoxetine. Thus, PET studies obtained with [ 11 C](+)McN5652/largely represent the regional distribution of the serotonin transporters and the inactive enantiomer [ 11 C](−)McN5652 shows the distribution of its nonspecific binding.
Robert F. Dannals - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Detection of Short- and Long-Term MDMA Neurotoxicity—A Positron Emission Tomography Study in the Living Baboon Brain
2013Co-Authors: Ursula Scheffel, Zsolt Szabo, William B. Mathews, Paige A. Finley, Robert F. Dannals, Hayden T. Ravert, Katalina Szabo, Jie Yuan, George A. RicaurteAbstract:ABSTRACT The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [ 11C](�)McN 5652, a potent 5-HT transporter ligand, as well as [ 11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [ 11C](�)McN5652, [ 11C](�)McN5652 (the inactive enantiomer of the active enantiomer [ 11C](�)McN5652) and [ 11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [ 11C](�)McN 5652, but not with [ 11C](�)McN5652 or [ 11C]RTI-55. Reductions in specific [ 11C](�)McN5652 binding (calculated as the difference in radioactivity concentrations between (�) and (�) [ 11C]McN5652) ranged from 44 % in the pons to 89 % in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measure
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quantitative positron emission tomography studies of the serotonin transporter in humans previously treated with the appetite suppressants fenfluramine or dexfenfluramine
Molecular Imaging and Biology, 2007Co-Authors: Una D Mccann, Zsolt Szabo, Robert F. Dannals, Melin Vranesic, Esen Seckin, Gary S Wand, Anna Duval, George A. RicaurteAbstract:Purpose The appetite suppressants fenfluramine and dexfenfluramine were widely prescribed before being withdrawn from the market in 1997. Both drugs are known to have the potential to damage brain serotonin (5-HT) axons and axon terminals in animals, including nonhuman primates. This study used quantitative positron emission tomography (PET) with [11C] McN5652, a serotonin transporter (SERT) ligand to determine whether humans previously exposed to fenfluramines showed reductions in SERT binding parameters.
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quantitative pet studies of the serotonin transporter in mdma users and controls using 11c McN5652 and 11c dasb
Neuropsychopharmacology, 2005Co-Authors: Una D Mccann, Zsolt Szabo, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Esen Seckin, P L Rosenblatt, George A. RicaurteAbstract:(±)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 [11C]McN5652 and [11C]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 (DVspec 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 [11C] McN5652 and [11C]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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comparison of 11c McN5652 and 11c dasb as serotonin transporter radioligands under various experimental conditions
The Journal of Nuclear Medicine, 2002Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Alan A Wilson, Una D Mccann, Taofeek K Owonikoko, John Hilton, George A. RicaurteAbstract:The brain serotonin (5-HT) system has been implicated in several neuropsychiatric conditions, including major depression, anxiety, obsessive compulsive disorder, and schizophrenia. Because of the perceived importance of the brain 5-HT system in these diseases, as well as a variety of normal brain functions (e.g., appetite, sleep), there has been considerable interest in developing neuroimaging techniques that permit assessment of 5-HT neurons in the living human brain. To this end, several research teams have developed and evaluated various SPECT and PET radiotracers for measurements of various components of the brain 5-HT system (1-6). With regard to PET, a series of radioligands showing high binding to the 5-HT transporter (SERT) in vitro have been evaluated, but most have been found to have insufficient specificity or selectivity for the SERT in vivo (7). To date, one of the more promising PET SERT radioligands identified is trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-11C-McN5652). (+)-11C-McN5652 binds selectively to the SERT, and its regional distribution of binding in humans correlates well with the known distribution of the SERT in human brain (8-10). In addition, studies in baboons and humans exposed to the brain 5-HT neurotoxin, (±)-3,4-methylenedioxymethamphetamine (MDMA), show significant reductions in (+)-11C-McN5652 binding (11-13). However, usefulness of (+)-11C-McN5652 may be limited by its nonspecific binding and slow release from specific binding sites (14,15). There have been recent reports that an alternative SERT radioligand,3-11C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (11C-DASB), holds promise for use as a SERT PET ligand (16,17). Preclinical studies indicate that, like (+)-11C-McN5652, 11C-DASB has high affinity and selectivity for the SERT in vitro and that, in vivo, it shows saturable and selective binding to the SERT in rodents. Also, damage of 5-HT axon terminals with the neurotoxin p-chloroamphetamine is associated with significant reductions in 11C-DASB binding in vivo in rodents, and low concentrations of radioactive metabolites in rat brain relative to the parent compound (17) suggest that this radioligand holds significant potential for use in evaluating the status of the brain SERT in humans. Notably, initial PET studies in humans (18) indicate that 11C-DASB has highly suitable characteristics for evaluating the status of the SERT in clinical settings and that 11C-DASB can successfully detect SERT occupancy by paroxetine and citalopram (19). The purpose of this study was to compare (+)-11C-McN5652 and 11C-DASB as PET ligands of the SERT in nonhuman primates. In particular, we sought to (a) compare binding characteristics of both radioligands to the SERT in a saline-treated baboon (normal SERT density), (b) compare the ability of the 2 radioligands to detect reductions in SERT density induced by the selective 5-HT neurotoxin MDMA, (c) evaluate the capability of both ligands to detect reduced SERT availability after pretreatment with paroxetine, and (d) determine how binding parameters of the 2 radioligands correlate with direct measures of brain 5-HT axonal markers measured ex vivo.
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kinetic analysis of 11c McN5652 a serotonin transporter radioligand
Journal of Cerebral Blood Flow and Metabolism, 1999Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Hayden T. Ravert, Katalina Szabo, George A. Ricaurte, Michael A Kraut, Sally C Palmon, Robert F. DannalsAbstract:The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)-McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](–)-McN5652. The impulse response function was calculated by deconvolution analysis of regional time–activity curves, and its peak value (fmax), its retention value at 75 minutes (fT), and its normalized retention (frel = fT/fmax) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DVT) and its specific binding component (DVs). Both the noncompartmental (fT, frel) and the compartmental parameters (DV) were investigated with and without...
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In Vivo Detection of Short- and Long-Term MDMA Neurotoxicity—A Positron Emission Tomography Study in the Living Baboon Brain
2013Co-Authors: Ursula Scheffel, Zsolt Szabo, William B. Mathews, Paige A. Finley, Robert F. Dannals, Hayden T. Ravert, Katalina Szabo, Jie Yuan, George A. RicaurteAbstract:ABSTRACT The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [ 11C](�)McN 5652, a potent 5-HT transporter ligand, as well as [ 11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [ 11C](�)McN5652, [ 11C](�)McN5652 (the inactive enantiomer of the active enantiomer [ 11C](�)McN5652) and [ 11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [ 11C](�)McN 5652, but not with [ 11C](�)McN5652 or [ 11C]RTI-55. Reductions in specific [ 11C](�)McN5652 binding (calculated as the difference in radioactivity concentrations between (�) and (�) [ 11C]McN5652) ranged from 44 % in the pons to 89 % in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measure
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quantitative pet studies of the serotonin transporter in mdma users and controls using 11c McN5652 and 11c dasb
Neuropsychopharmacology, 2005Co-Authors: Una D Mccann, Zsolt Szabo, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Esen Seckin, P L Rosenblatt, George A. RicaurteAbstract:(±)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 [11C]McN5652 and [11C]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 (DVspec 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 [11C] McN5652 and [11C]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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comparison of 11c McN5652 and 11c dasb as serotonin transporter radioligands under various experimental conditions
The Journal of Nuclear Medicine, 2002Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Alan A Wilson, Una D Mccann, Taofeek K Owonikoko, John Hilton, George A. RicaurteAbstract:The brain serotonin (5-HT) system has been implicated in several neuropsychiatric conditions, including major depression, anxiety, obsessive compulsive disorder, and schizophrenia. Because of the perceived importance of the brain 5-HT system in these diseases, as well as a variety of normal brain functions (e.g., appetite, sleep), there has been considerable interest in developing neuroimaging techniques that permit assessment of 5-HT neurons in the living human brain. To this end, several research teams have developed and evaluated various SPECT and PET radiotracers for measurements of various components of the brain 5-HT system (1-6). With regard to PET, a series of radioligands showing high binding to the 5-HT transporter (SERT) in vitro have been evaluated, but most have been found to have insufficient specificity or selectivity for the SERT in vivo (7). To date, one of the more promising PET SERT radioligands identified is trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-11C-McN5652). (+)-11C-McN5652 binds selectively to the SERT, and its regional distribution of binding in humans correlates well with the known distribution of the SERT in human brain (8-10). In addition, studies in baboons and humans exposed to the brain 5-HT neurotoxin, (±)-3,4-methylenedioxymethamphetamine (MDMA), show significant reductions in (+)-11C-McN5652 binding (11-13). However, usefulness of (+)-11C-McN5652 may be limited by its nonspecific binding and slow release from specific binding sites (14,15). There have been recent reports that an alternative SERT radioligand,3-11C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (11C-DASB), holds promise for use as a SERT PET ligand (16,17). Preclinical studies indicate that, like (+)-11C-McN5652, 11C-DASB has high affinity and selectivity for the SERT in vitro and that, in vivo, it shows saturable and selective binding to the SERT in rodents. Also, damage of 5-HT axon terminals with the neurotoxin p-chloroamphetamine is associated with significant reductions in 11C-DASB binding in vivo in rodents, and low concentrations of radioactive metabolites in rat brain relative to the parent compound (17) suggest that this radioligand holds significant potential for use in evaluating the status of the brain SERT in humans. Notably, initial PET studies in humans (18) indicate that 11C-DASB has highly suitable characteristics for evaluating the status of the SERT in clinical settings and that 11C-DASB can successfully detect SERT occupancy by paroxetine and citalopram (19). The purpose of this study was to compare (+)-11C-McN5652 and 11C-DASB as PET ligands of the SERT in nonhuman primates. In particular, we sought to (a) compare binding characteristics of both radioligands to the SERT in a saline-treated baboon (normal SERT density), (b) compare the ability of the 2 radioligands to detect reductions in SERT density induced by the selective 5-HT neurotoxin MDMA, (c) evaluate the capability of both ligands to detect reduced SERT availability after pretreatment with paroxetine, and (d) determine how binding parameters of the 2 radioligands correlate with direct measures of brain 5-HT axonal markers measured ex vivo.
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kinetic analysis of 11c McN5652 a serotonin transporter radioligand
Journal of Cerebral Blood Flow and Metabolism, 1999Co-Authors: Zsolt Szabo, Ursula Scheffel, William B. Mathews, Hayden T. Ravert, Katalina Szabo, George A. Ricaurte, Michael A Kraut, Sally C Palmon, Robert F. DannalsAbstract:The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)-McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](–)-McN5652. The impulse response function was calculated by deconvolution analysis of regional time–activity curves, and its peak value (fmax), its retention value at 75 minutes (fT), and its normalized retention (frel = fT/fmax) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DVT) and its specific binding component (DVs). Both the noncompartmental (fT, frel) and the compartmental parameters (DV) were investigated with and without...
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in vivo detection of short and long term mdma neurotoxicity a positron emission tomography study in the living baboon brain
Synapse, 1998Co-Authors: Ursula Scheffel, Zsolt Szabo, William B. Mathews, Robert F. Dannals, Hayden T. Ravert, Katalina Szabo, Jie Yuan, Paige Finley, George A. RicaurteAbstract:The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [11C](+)McN 5652, a potent 5-HT transporter ligand, as well as [11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [11C](+)McN5652, [11C](−)McN5652 (the inactive enantiomer of the active enantiomer [11C](+)McN5652) and [11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [11C](+)McN 5652, but not with [11C](−)McN5652 or [11C]RTI-55. Reductions in specific [11C](+)McN5652 binding (calculated as the difference in radioactivity concentrations between (+) and (−)[11C]McN5652) ranged from 44% in the pons to 89% in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measured after sacrifice of the animal. The results of these studies indicate that PET imaging of the living nonhuman primate brain with [11C](+)McN 5652 can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity. Using PET, it should also be feasible to use [11C](+)McN5652 to determine whether human MDMA users are also susceptible to MDMA's neurotoxic effects. Synapse 29:183–192, 1998. © 1998 Wiley-Liss, Inc.