The Experts below are selected from a list of 48 Experts worldwide ranked by ideXlab platform
Sylvie Chalon - One of the best experts on this subject based on the ideXlab platform.
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Exploration of the Dopamine Transporter: In Vitro and In Vivo Characterization of a High-Affinity and High-Specificity Iodinated Tropane Derivative (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy- 3β-(4′-methylphenyl)norTropane (PE2I)
Nuclear medicine and biology, 1998Co-Authors: Denis Guilloteau, Lucette Garreau, Patrick Emond, Y Frangin, J L Baulieu, L. Pourcelot, Laurent Mauclaire, Jean-claude Besnard, Sylvie ChalonAbstract:Abstract For the diagnosis and follow-up of neurodegenerative diseases, many cocaine Derivatives have been proposed as radioligands to explore the dopamine transporter. As none of them have all the criteria of specificity and kinetics for human use, we have developed a new Derivative, ( E )- N -(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)norTropane (PE2I), which displays promising properties. We report the characterization of PE2I in vitro on rat striatal membranes and in vivo in rats and in monkeys. PE2I had a high affinity (Kd = 0.09 ± 0.01 nM) and high specificity for the dopamine transporter. In rats we observed a high accumulation in the striatum; by contrast, a very low fixation was measured in the cortex. Moreover, a preinjection of a saturating dose of GBR 12909 prevented the striatal accumulation of PE2I by 74%. These results confirmed the specificity of PE2I for the dopamine transporter. In vivo in monkeys, SPECT studies showed a high accumulation in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamine transporter exploration by SPECT using a single-day protocol.
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n 3 iodoprop 2e enyl 2β carbomethoxy 3β 3 4 dichlorophenyl norTropane β cdit a Tropane Derivative pharmacological characterization as a specific ligand for the dopamine transporter in the rodent brain
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Lucette Garreau, Patrick Emond, Catherine Belzung, Denis Guilloteau, Y Frangin, J C Besnard, Sylvie ChalonAbstract:N-(3-Iodoprop-2 E -enyl)-2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)norTropane (β-CDIT), a new iodinated Tropane Derivative, has been synthesized and radiolabeled with iodine. [ 125 I]β-CDIT was tested in vitro and ex vivo as a probe for the dopamine transporter site in the rat brain, and behavioral studies were performed in mice. Saturation studies in the striatum revealed that [ 125 I]β-CDIT bound to a single high-affinity site. The K d value was 0.18 ± 0.07 nM, and the corresponding B max value was 500 ± 80 fmol/mg of protein. The pharmacological profile of specific [ 125 I]β-CDIT binding in the striatum was consistent with that of the dopamine transporter. In addition, competition studies in cerebral cortex regions with [ 3 H]paroxetine and [ 3 H]nisoxetine showed a very low affinity of β-CDIT for the 5-hydroxytryptamine ( K i = 50 nM) and norepinephrine ( K i = 500 nM) transporters compared with β-CIT (corresponding K i values were 3 and 80 nM). In contrast, the competition of β-CDIT with [ 3 H]GBR 12935 in the striatal region ( K i = 29 nM) was of the same order of value as for β-CIT ( K i = 27.5 nM). Behavioral experiments in mice showed that both β-CDIT and β-CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [ 125 I]β-CDIT demonstrated high densities of [ 125 I]β-CDIT binding sites in areas known to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [ 125 I]β-CDIT should be a valuable ligand for the exploration of the dopamine transporter with single-photon emission computed tomography.
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a new iodinated Tropane Derivative beta cdit for in vivo dopamine transporter exploration comparison with beta cit
Synapse, 1997Co-Authors: Patrick Emond, Lucette Garreau, Y Frangin, J C Besnard, Sylvie Chalon, Annemarie Dognon, Sylvie Bodard, J L Baulieu, Dennis GuilloteauAbstract:SPECT exploration of the dopamine transporter with Tropane Derivatives such as β-CIT has already produced very valuable information in humans. However, the high affinity of this tracer for both dopamine and serotonin transporters and its slow in vivo kinetics provide the best images in humans more than 20 h after injection. In order to improve those properties, we performed structural changes in the Tropane structure in the phenyl and nitrogen substituents for higher affinity and specificity and obtained a promising ligand, 2β-carbomethoxy-3β-(3′, 4′ diclorophenyl)-8-(3-iodoprop-2E-enyl) norTropane (β-CDIT). This iodinated ligand was characterized in vitro and in vivo in the rat in comparison with β-CIT. In vitro competition studies revealed that β-CIT and β-CDIT similarly inhibited the binding of [3H]GBR 12935 (Ki = 27.5 and 29.0 nM, respectively). In contrast, competition studies with [3H]paroxetine and [3H]nisoxetine showed that β-CDIT had a lower affinity for the serotonin transporter than β-CIT (Ki = 50 and 3 nM, respectively) and also a lower affinity for the noradrenaline transporter than β-CIT (Ki = 500 and 80 nM, respectively). In vivo studies in the rat showed that there was high and rapid uptake of [125I] β-CDIT in the striatum. In addition, preinjection of GBR 12909 prevented accumulation of this ligand in the striatum by 80%, whereas only a 30% decrease was obtained for [125I]β-CIT. It seems, therefore, that the combination of aromatic and nitrogen substitution improves the properties of Tropane Derivatives to provide an exclusive dopamine transporter ligand potentially usable in SPECT. Synapse 26:72–80, 1997. © 1997 Wiley-Liss, Inc.
Lucette Garreau - One of the best experts on this subject based on the ideXlab platform.
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Exploration of the Dopamine Transporter: In Vitro and In Vivo Characterization of a High-Affinity and High-Specificity Iodinated Tropane Derivative (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy- 3β-(4′-methylphenyl)norTropane (PE2I)
Nuclear medicine and biology, 1998Co-Authors: Denis Guilloteau, Lucette Garreau, Patrick Emond, Y Frangin, J L Baulieu, L. Pourcelot, Laurent Mauclaire, Jean-claude Besnard, Sylvie ChalonAbstract:Abstract For the diagnosis and follow-up of neurodegenerative diseases, many cocaine Derivatives have been proposed as radioligands to explore the dopamine transporter. As none of them have all the criteria of specificity and kinetics for human use, we have developed a new Derivative, ( E )- N -(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)norTropane (PE2I), which displays promising properties. We report the characterization of PE2I in vitro on rat striatal membranes and in vivo in rats and in monkeys. PE2I had a high affinity (Kd = 0.09 ± 0.01 nM) and high specificity for the dopamine transporter. In rats we observed a high accumulation in the striatum; by contrast, a very low fixation was measured in the cortex. Moreover, a preinjection of a saturating dose of GBR 12909 prevented the striatal accumulation of PE2I by 74%. These results confirmed the specificity of PE2I for the dopamine transporter. In vivo in monkeys, SPECT studies showed a high accumulation in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamine transporter exploration by SPECT using a single-day protocol.
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n 3 iodoprop 2e enyl 2β carbomethoxy 3β 3 4 dichlorophenyl norTropane β cdit a Tropane Derivative pharmacological characterization as a specific ligand for the dopamine transporter in the rodent brain
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Lucette Garreau, Patrick Emond, Catherine Belzung, Denis Guilloteau, Y Frangin, J C Besnard, Sylvie ChalonAbstract:N-(3-Iodoprop-2 E -enyl)-2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)norTropane (β-CDIT), a new iodinated Tropane Derivative, has been synthesized and radiolabeled with iodine. [ 125 I]β-CDIT was tested in vitro and ex vivo as a probe for the dopamine transporter site in the rat brain, and behavioral studies were performed in mice. Saturation studies in the striatum revealed that [ 125 I]β-CDIT bound to a single high-affinity site. The K d value was 0.18 ± 0.07 nM, and the corresponding B max value was 500 ± 80 fmol/mg of protein. The pharmacological profile of specific [ 125 I]β-CDIT binding in the striatum was consistent with that of the dopamine transporter. In addition, competition studies in cerebral cortex regions with [ 3 H]paroxetine and [ 3 H]nisoxetine showed a very low affinity of β-CDIT for the 5-hydroxytryptamine ( K i = 50 nM) and norepinephrine ( K i = 500 nM) transporters compared with β-CIT (corresponding K i values were 3 and 80 nM). In contrast, the competition of β-CDIT with [ 3 H]GBR 12935 in the striatal region ( K i = 29 nM) was of the same order of value as for β-CIT ( K i = 27.5 nM). Behavioral experiments in mice showed that both β-CDIT and β-CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [ 125 I]β-CDIT demonstrated high densities of [ 125 I]β-CDIT binding sites in areas known to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [ 125 I]β-CDIT should be a valuable ligand for the exploration of the dopamine transporter with single-photon emission computed tomography.
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a new iodinated Tropane Derivative beta cdit for in vivo dopamine transporter exploration comparison with beta cit
Synapse, 1997Co-Authors: Patrick Emond, Lucette Garreau, Y Frangin, J C Besnard, Sylvie Chalon, Annemarie Dognon, Sylvie Bodard, J L Baulieu, Dennis GuilloteauAbstract:SPECT exploration of the dopamine transporter with Tropane Derivatives such as β-CIT has already produced very valuable information in humans. However, the high affinity of this tracer for both dopamine and serotonin transporters and its slow in vivo kinetics provide the best images in humans more than 20 h after injection. In order to improve those properties, we performed structural changes in the Tropane structure in the phenyl and nitrogen substituents for higher affinity and specificity and obtained a promising ligand, 2β-carbomethoxy-3β-(3′, 4′ diclorophenyl)-8-(3-iodoprop-2E-enyl) norTropane (β-CDIT). This iodinated ligand was characterized in vitro and in vivo in the rat in comparison with β-CIT. In vitro competition studies revealed that β-CIT and β-CDIT similarly inhibited the binding of [3H]GBR 12935 (Ki = 27.5 and 29.0 nM, respectively). In contrast, competition studies with [3H]paroxetine and [3H]nisoxetine showed that β-CDIT had a lower affinity for the serotonin transporter than β-CIT (Ki = 50 and 3 nM, respectively) and also a lower affinity for the noradrenaline transporter than β-CIT (Ki = 500 and 80 nM, respectively). In vivo studies in the rat showed that there was high and rapid uptake of [125I] β-CDIT in the striatum. In addition, preinjection of GBR 12909 prevented accumulation of this ligand in the striatum by 80%, whereas only a 30% decrease was obtained for [125I]β-CIT. It seems, therefore, that the combination of aromatic and nitrogen substitution improves the properties of Tropane Derivatives to provide an exclusive dopamine transporter ligand potentially usable in SPECT. Synapse 26:72–80, 1997. © 1997 Wiley-Liss, Inc.
Grace Samuel - One of the best experts on this subject based on the ideXlab platform.
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correlative 99m tc labeled Tropane Derivative single photon emission computer tomography and clinical assessment in the staging of parkinson disease
World journal of nuclear medicine, 2014Co-Authors: Ajit Sugunan Shinto, Joppy Antony, Koramadai Karuppuswamy Kamaleshwaran, Krishnan Vijayan, Arul Selvan, Aruna Korde, Mythili Kameshwaran, Grace SamuelAbstract:Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a selective loss of dopamine in the striatum. Problems remain in the accurate diagnosis of PD. The diagnosis of idiopathic PD is based on the interpretation of clinical signs and symptoms could be incorrect at the time of initial presentation. In vivo imaging of the dopaminergic system has the potential to improve the diagnosis of PD in its early stages. The imaging of dopamine transporter (DAT) with 99m Tc-labeled Tropane Derivative (TRODAT-1) single photon emission computer tomography/computer tomography (SPECT/CT) has been proposed to be a valuable and feasible means of assessment of the integrity of dopamine neurons. The purpose of this study was to investigate the potential usefulness of 99m Tc-TRODAT-1 imaging in the evaluation of patients with PD and classify into different stages of the disease. SPECT imaging with 99m Tc-TRODAT-1 was conducted in 16 consecutive PD patients (9 men; 7 women) and in 6 age matched healthy volunteers (4 men; 2 women). The images were obtained 3 h after the intra-venous injection of the tracer. Specific uptake in the striatum and its sub-regions, including the putamen and caudate nucleus was calculated and the ratios of specific striatal binding to nonspecific occipital binding were calculated. ANOVA with Dunnett C post - hoc analysis was conducted using SPSS 20. A stepwise reduction in specific striatal uptake of 99m Tc-TRODAT-1 with increasing disease severity between healthy control versus Stage I versus Stage II versus Stage III was found in PD patients (i.e., 3.77 vs. 2.56 vs. 1.57 vs. 0.63, P P P 99m Tc-TRODAT-1 is accurate and widely available for the assessment of DAT activity, which might shed light on the integrity of the presynaptic nigrostriatal function. Our preliminary study results confirm the potential of using 99m Tc-TRODAT-1 for DAT measurement, which is clinically important for the staging of PD.
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Correlative 99m Tc-labeled Tropane Derivative single photon emission computer tomography and clinical assessment in the staging of parkinson disease
'Medknow', 2014Co-Authors: Ajit Sugunan Shinto, Joppy Antony, Koramadai Karuppuswamy Kamaleshwaran, Krishnan Vijayan, Arul Selvan, Aruna Korde, Mythili Kameshwaran, Grace SamuelAbstract:Parkinson′s disease (PD) is a progressive neurodegenerative disorder characterized by a selective loss of dopamine in the striatum. Problems remain in the accurate diagnosis of PD. The diagnosis of idiopathic PD is based on the interpretation of clinical signs and symptoms could be incorrect at the time of initial presentation. In vivo imaging of the dopaminergic system has the potential to improve the diagnosis of PD in its early stages. The imaging of dopamine transporter (DAT) with 99m Tc-labeled Tropane Derivative (TRODAT-1) single photon emission computer tomography/computer tomography (SPECT/CT) has been proposed to be a valuable and feasible means of assessment of the integrity of dopamine neurons. The purpose of this study was to investigate the potential usefulness of 99m Tc-TRODAT-1 imaging in the evaluation of patients with PD and classify into different stages of the disease. SPECT imaging with 99m Tc-TRODAT-1 was conducted in 16 consecutive PD patients (9 men; 7 women) and in 6 age matched healthy volunteers (4 men; 2 women). The images were obtained 3 h after the intra-venous injection of the tracer. Specific uptake in the striatum and its sub-regions, including the putamen and caudate nucleus was calculated and the ratios of specific striatal binding to nonspecific occipital binding were calculated. ANOVA with Dunnett C post-hoc analysis was conducted using SPSS 20. A stepwise reduction in specific striatal uptake of 99m Tc-TRODAT-1 with increasing disease severity between healthy control versus Stage I versus Stage II versus Stage III was found in PD patients (i.e., 3.77 vs. 2.56 vs. 1.57 vs. 0.63, P < 0.05). The changes were magnified by measurement of specific putaminal uptake (1.43 vs. 0.79 vs. 0.54 vs. 0.19, P < 0.05) and specific caudate uptake (1.90 vs. 1.47 vs. 0.73 vs. 0.27, P < 0.05). No remarkable adverse reactions were found in either healthy volunteers or PD patients during or after imaging. 99m Tc-TRODAT-1 is accurate and widely available for the assessment of DAT activity, which might shed light on the integrity of the presynaptic nigrostriatal function. Our preliminary study results confirm the potential of using 99m Tc-TRODAT-1 for DAT measurement, which is clinically important for the staging of PD
Patrick Emond - One of the best experts on this subject based on the ideXlab platform.
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Exploration of the Dopamine Transporter: In Vitro and In Vivo Characterization of a High-Affinity and High-Specificity Iodinated Tropane Derivative (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy- 3β-(4′-methylphenyl)norTropane (PE2I)
Nuclear medicine and biology, 1998Co-Authors: Denis Guilloteau, Lucette Garreau, Patrick Emond, Y Frangin, J L Baulieu, L. Pourcelot, Laurent Mauclaire, Jean-claude Besnard, Sylvie ChalonAbstract:Abstract For the diagnosis and follow-up of neurodegenerative diseases, many cocaine Derivatives have been proposed as radioligands to explore the dopamine transporter. As none of them have all the criteria of specificity and kinetics for human use, we have developed a new Derivative, ( E )- N -(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)norTropane (PE2I), which displays promising properties. We report the characterization of PE2I in vitro on rat striatal membranes and in vivo in rats and in monkeys. PE2I had a high affinity (Kd = 0.09 ± 0.01 nM) and high specificity for the dopamine transporter. In rats we observed a high accumulation in the striatum; by contrast, a very low fixation was measured in the cortex. Moreover, a preinjection of a saturating dose of GBR 12909 prevented the striatal accumulation of PE2I by 74%. These results confirmed the specificity of PE2I for the dopamine transporter. In vivo in monkeys, SPECT studies showed a high accumulation in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamine transporter exploration by SPECT using a single-day protocol.
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n 3 iodoprop 2e enyl 2β carbomethoxy 3β 3 4 dichlorophenyl norTropane β cdit a Tropane Derivative pharmacological characterization as a specific ligand for the dopamine transporter in the rodent brain
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Lucette Garreau, Patrick Emond, Catherine Belzung, Denis Guilloteau, Y Frangin, J C Besnard, Sylvie ChalonAbstract:N-(3-Iodoprop-2 E -enyl)-2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)norTropane (β-CDIT), a new iodinated Tropane Derivative, has been synthesized and radiolabeled with iodine. [ 125 I]β-CDIT was tested in vitro and ex vivo as a probe for the dopamine transporter site in the rat brain, and behavioral studies were performed in mice. Saturation studies in the striatum revealed that [ 125 I]β-CDIT bound to a single high-affinity site. The K d value was 0.18 ± 0.07 nM, and the corresponding B max value was 500 ± 80 fmol/mg of protein. The pharmacological profile of specific [ 125 I]β-CDIT binding in the striatum was consistent with that of the dopamine transporter. In addition, competition studies in cerebral cortex regions with [ 3 H]paroxetine and [ 3 H]nisoxetine showed a very low affinity of β-CDIT for the 5-hydroxytryptamine ( K i = 50 nM) and norepinephrine ( K i = 500 nM) transporters compared with β-CIT (corresponding K i values were 3 and 80 nM). In contrast, the competition of β-CDIT with [ 3 H]GBR 12935 in the striatal region ( K i = 29 nM) was of the same order of value as for β-CIT ( K i = 27.5 nM). Behavioral experiments in mice showed that both β-CDIT and β-CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [ 125 I]β-CDIT demonstrated high densities of [ 125 I]β-CDIT binding sites in areas known to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [ 125 I]β-CDIT should be a valuable ligand for the exploration of the dopamine transporter with single-photon emission computed tomography.
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a new iodinated Tropane Derivative beta cdit for in vivo dopamine transporter exploration comparison with beta cit
Synapse, 1997Co-Authors: Patrick Emond, Lucette Garreau, Y Frangin, J C Besnard, Sylvie Chalon, Annemarie Dognon, Sylvie Bodard, J L Baulieu, Dennis GuilloteauAbstract:SPECT exploration of the dopamine transporter with Tropane Derivatives such as β-CIT has already produced very valuable information in humans. However, the high affinity of this tracer for both dopamine and serotonin transporters and its slow in vivo kinetics provide the best images in humans more than 20 h after injection. In order to improve those properties, we performed structural changes in the Tropane structure in the phenyl and nitrogen substituents for higher affinity and specificity and obtained a promising ligand, 2β-carbomethoxy-3β-(3′, 4′ diclorophenyl)-8-(3-iodoprop-2E-enyl) norTropane (β-CDIT). This iodinated ligand was characterized in vitro and in vivo in the rat in comparison with β-CIT. In vitro competition studies revealed that β-CIT and β-CDIT similarly inhibited the binding of [3H]GBR 12935 (Ki = 27.5 and 29.0 nM, respectively). In contrast, competition studies with [3H]paroxetine and [3H]nisoxetine showed that β-CDIT had a lower affinity for the serotonin transporter than β-CIT (Ki = 50 and 3 nM, respectively) and also a lower affinity for the noradrenaline transporter than β-CIT (Ki = 500 and 80 nM, respectively). In vivo studies in the rat showed that there was high and rapid uptake of [125I] β-CDIT in the striatum. In addition, preinjection of GBR 12909 prevented accumulation of this ligand in the striatum by 80%, whereas only a 30% decrease was obtained for [125I]β-CIT. It seems, therefore, that the combination of aromatic and nitrogen substitution improves the properties of Tropane Derivatives to provide an exclusive dopamine transporter ligand potentially usable in SPECT. Synapse 26:72–80, 1997. © 1997 Wiley-Liss, Inc.
Y Frangin - One of the best experts on this subject based on the ideXlab platform.
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Exploration of the Dopamine Transporter: In Vitro and In Vivo Characterization of a High-Affinity and High-Specificity Iodinated Tropane Derivative (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy- 3β-(4′-methylphenyl)norTropane (PE2I)
Nuclear medicine and biology, 1998Co-Authors: Denis Guilloteau, Lucette Garreau, Patrick Emond, Y Frangin, J L Baulieu, L. Pourcelot, Laurent Mauclaire, Jean-claude Besnard, Sylvie ChalonAbstract:Abstract For the diagnosis and follow-up of neurodegenerative diseases, many cocaine Derivatives have been proposed as radioligands to explore the dopamine transporter. As none of them have all the criteria of specificity and kinetics for human use, we have developed a new Derivative, ( E )- N -(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)norTropane (PE2I), which displays promising properties. We report the characterization of PE2I in vitro on rat striatal membranes and in vivo in rats and in monkeys. PE2I had a high affinity (Kd = 0.09 ± 0.01 nM) and high specificity for the dopamine transporter. In rats we observed a high accumulation in the striatum; by contrast, a very low fixation was measured in the cortex. Moreover, a preinjection of a saturating dose of GBR 12909 prevented the striatal accumulation of PE2I by 74%. These results confirmed the specificity of PE2I for the dopamine transporter. In vivo in monkeys, SPECT studies showed a high accumulation in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamine transporter exploration by SPECT using a single-day protocol.
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n 3 iodoprop 2e enyl 2β carbomethoxy 3β 3 4 dichlorophenyl norTropane β cdit a Tropane Derivative pharmacological characterization as a specific ligand for the dopamine transporter in the rodent brain
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Lucette Garreau, Patrick Emond, Catherine Belzung, Denis Guilloteau, Y Frangin, J C Besnard, Sylvie ChalonAbstract:N-(3-Iodoprop-2 E -enyl)-2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)norTropane (β-CDIT), a new iodinated Tropane Derivative, has been synthesized and radiolabeled with iodine. [ 125 I]β-CDIT was tested in vitro and ex vivo as a probe for the dopamine transporter site in the rat brain, and behavioral studies were performed in mice. Saturation studies in the striatum revealed that [ 125 I]β-CDIT bound to a single high-affinity site. The K d value was 0.18 ± 0.07 nM, and the corresponding B max value was 500 ± 80 fmol/mg of protein. The pharmacological profile of specific [ 125 I]β-CDIT binding in the striatum was consistent with that of the dopamine transporter. In addition, competition studies in cerebral cortex regions with [ 3 H]paroxetine and [ 3 H]nisoxetine showed a very low affinity of β-CDIT for the 5-hydroxytryptamine ( K i = 50 nM) and norepinephrine ( K i = 500 nM) transporters compared with β-CIT (corresponding K i values were 3 and 80 nM). In contrast, the competition of β-CDIT with [ 3 H]GBR 12935 in the striatal region ( K i = 29 nM) was of the same order of value as for β-CIT ( K i = 27.5 nM). Behavioral experiments in mice showed that both β-CDIT and β-CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [ 125 I]β-CDIT demonstrated high densities of [ 125 I]β-CDIT binding sites in areas known to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [ 125 I]β-CDIT should be a valuable ligand for the exploration of the dopamine transporter with single-photon emission computed tomography.
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a new iodinated Tropane Derivative beta cdit for in vivo dopamine transporter exploration comparison with beta cit
Synapse, 1997Co-Authors: Patrick Emond, Lucette Garreau, Y Frangin, J C Besnard, Sylvie Chalon, Annemarie Dognon, Sylvie Bodard, J L Baulieu, Dennis GuilloteauAbstract:SPECT exploration of the dopamine transporter with Tropane Derivatives such as β-CIT has already produced very valuable information in humans. However, the high affinity of this tracer for both dopamine and serotonin transporters and its slow in vivo kinetics provide the best images in humans more than 20 h after injection. In order to improve those properties, we performed structural changes in the Tropane structure in the phenyl and nitrogen substituents for higher affinity and specificity and obtained a promising ligand, 2β-carbomethoxy-3β-(3′, 4′ diclorophenyl)-8-(3-iodoprop-2E-enyl) norTropane (β-CDIT). This iodinated ligand was characterized in vitro and in vivo in the rat in comparison with β-CIT. In vitro competition studies revealed that β-CIT and β-CDIT similarly inhibited the binding of [3H]GBR 12935 (Ki = 27.5 and 29.0 nM, respectively). In contrast, competition studies with [3H]paroxetine and [3H]nisoxetine showed that β-CDIT had a lower affinity for the serotonin transporter than β-CIT (Ki = 50 and 3 nM, respectively) and also a lower affinity for the noradrenaline transporter than β-CIT (Ki = 500 and 80 nM, respectively). In vivo studies in the rat showed that there was high and rapid uptake of [125I] β-CDIT in the striatum. In addition, preinjection of GBR 12909 prevented accumulation of this ligand in the striatum by 80%, whereas only a 30% decrease was obtained for [125I]β-CIT. It seems, therefore, that the combination of aromatic and nitrogen substitution improves the properties of Tropane Derivatives to provide an exclusive dopamine transporter ligand potentially usable in SPECT. Synapse 26:72–80, 1997. © 1997 Wiley-Liss, Inc.
