The Experts below are selected from a list of 255 Experts worldwide ranked by ideXlab platform
Lyn S Pilowsky - One of the best experts on this subject based on the ideXlab platform.
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improved estimation of metabolite rate constants for sup 123 i Epidepride by simultaneous modelling
IEEE Nuclear Science Symposium, 2003Co-Authors: K Erlandsson, P J Ell, Robert B Innis, M Fujita, Lyn S PilowskyAbstract:We have previously identified a problem related to the use of the reference tissue model for quantification of the high affinity dopamine D/sub 2//D/sub 3/ receptor SPECT tracer [/sup 123/I]Epidepride. It has been noted that quantification of this tracer could be compromised by the presence of lipophilic metabolites crossing the blood-brain barrier. Using kinetic modelling with separate plasma input functions for parent tracer and metabolites, we have now investigated the effect that the metabolites would have on reference tissue modelling. To overcome the problem of poor identifiability of the metabolite rate constants, we have also investigated methods to obtain a better estimate of these rate constants by fitting the time-activity curves for two different brain regions simultaneously, and also by using two different models simultaneously. Our results show that the inclusion of the metabolites in the model for [/sup 123/I]Epidepride does improve the consistency of the results, suggesting that the metabolites do in fact enter the brain. Also, simultaneous modelling did reduce the variability of the metabolite rate constants, however this did not actually improve the performance of the model.
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is regionally selective d2 d3 dopamine occupancy sufficient for atypical antipsychotic effect an in vivo quantitative 123i Epidepride spet study of amisulpride treated patients
American Journal of Psychiatry, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Robert J Flanagan, Lyn S PilowskyAbstract:OBJECTIVE: Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D2-like receptors with modest striatal D2 receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D2/D3 dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors’ goal was to evaluate whether treatment with amisulpride results in “limbic selective” D2/D3 receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [123I]Epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of recepto...
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analysis of d2 dopamine receptor occupancy with quantitative spet using the high affinity ligand 123i Epidepride resolving conflicting findings
NeuroImage, 2003Co-Authors: K Erlandsson, Rachel S Mulligan, P J Ell, Lyn S Pilowsky, Rodrigo A Bressan, Vincent J CunninghamAbstract:Abstract Recent studies of limbic cortical dopamine D2 receptor occupancy by clozapine using high-affinity PET and SPET radioligands have produced conflicting findings. It has been suggested that these divergent findings are due to between-study differences in the method used to estimate D2 receptor-binding potential. We compared different methods for estimating striatal and temporal cortical D2 receptor occupancy with high-affinity tracers. In vivo experimental SPET data, obtained with [123I]Epidepride were analysed with reference tissue kinetic modeling and with the ratio method, applied to data corresponding to short (60 min) and long (240 min) acquisition times. Dopamine D2 receptor occupancy by the atypical antipsychotic drug risperidone was evaluated. Simulation experiments were also performed, comparing occupancy values obtained for different receptor densities in relation to different data acquisition times. The simulation results revealed that previously published data regarding errors in occupancy estimation by analysis of time activity data acquired for 60 min cannot be extrapolated to studies performed over 240 min. The ratio method provided accurate temporal cortical D2 receptor occupancy values when applied to data from a late time period, but underestimated the occupancy with earlier data. In striatum, both the late data ratio method and reference tissue kinetic modeling using all data underestimated D2 receptor occupancy. However, more accurate analyses of striatal D2 occupancy still showed selective limbic/cortical occupancy by risperidone. Our results substantiate the previous [123I]Epidepride findings of high temporal cortical occupancy by other atypical antipsychotic drugs and suggest that a potential source of conflicting findings might be short scanning times imposed by [11C]FLB 457, leading to underestimation of temporal cortical D2 receptor occupancy by this method.
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optimizing limbic selective d2 d3 receptor occupancy by risperidone a 123i Epidepride spet study
Journal of Clinical Psychopharmacology, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Lyn S PilowskyAbstract:Selective action at limbic cortical dopamine D2-like receptors is a putative mechanism of atypical antipsychotic efficacy with few extrapyramidal side effects. Although risperidone is an atypical antipsychotic with high affinity for D2 receptors, low-dose risperidone treatment is effective without inducing extrapyramidal symptoms. The objective was to test the hypothesis that treatment with low-dose risperidone results in 'limbic selective' D2/D3 receptor blockade in vivo. Dynamic single photon emission tomography (SPET) sequences were obtained over 5 hours after injection of [123I]-Epidepride (approximately 150 MBq), using a high-resolution triple-headed brain scanner (Marconi Prism 3000XP). Kinetic modelling was performed using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a normal volunteer control group (n = 5). Six patients treated with low-dose risperidone (mean = 2.6 mg) showed moderate levels of D2/D3 occupancy in striatum (49.9%), but higher levels of D2/D3 occupancy in thalamus (70.8%) and temporal cortex (75.2%). Occupancy values in striatum were significantly different from thalamus (F (1,4) = 26.3, p < 0.01) and from temporal cortex (F (1,4) = 53.4, p < 0.01). This is the first study to evaluate striatal and extrastriatal occupancy of risperidone. Low dose treatment with risperidone achieves a similar selectivity of limbic cortical over striatal D2/D3 receptor blockade to that of atypical antipsychotics with lower D2/D3 affinity such as clozapine, olanzapine and quetiapine. This finding is consistent with the relevance of 'limbic selective' D2/D3 receptor occupancy to the therapeutic efficacy of atypical antipsychotic drugs.
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striatal and extra striatal d 2 d 3 dopamine receptor occupancy by quetiapine in vivo 123 i Epidepride single photon emission tomography spet study
British Journal of Psychiatry, 2000Co-Authors: Caroline Stephenson, V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, H M Jones, Lyn S PilowskyAbstract:Background Selective action at limbic cortical dopamine D2-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects. Aims To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo . Method The high-affinity D2/D3 ligand [123I]-Epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients ( n =6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared. Results Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than typical antipsychotics. Conclusions Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for atypical drug action.
P J Ell - One of the best experts on this subject based on the ideXlab platform.
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improved estimation of metabolite rate constants for sup 123 i Epidepride by simultaneous modelling
IEEE Nuclear Science Symposium, 2003Co-Authors: K Erlandsson, P J Ell, Robert B Innis, M Fujita, Lyn S PilowskyAbstract:We have previously identified a problem related to the use of the reference tissue model for quantification of the high affinity dopamine D/sub 2//D/sub 3/ receptor SPECT tracer [/sup 123/I]Epidepride. It has been noted that quantification of this tracer could be compromised by the presence of lipophilic metabolites crossing the blood-brain barrier. Using kinetic modelling with separate plasma input functions for parent tracer and metabolites, we have now investigated the effect that the metabolites would have on reference tissue modelling. To overcome the problem of poor identifiability of the metabolite rate constants, we have also investigated methods to obtain a better estimate of these rate constants by fitting the time-activity curves for two different brain regions simultaneously, and also by using two different models simultaneously. Our results show that the inclusion of the metabolites in the model for [/sup 123/I]Epidepride does improve the consistency of the results, suggesting that the metabolites do in fact enter the brain. Also, simultaneous modelling did reduce the variability of the metabolite rate constants, however this did not actually improve the performance of the model.
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is regionally selective d2 d3 dopamine occupancy sufficient for atypical antipsychotic effect an in vivo quantitative 123i Epidepride spet study of amisulpride treated patients
American Journal of Psychiatry, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Robert J Flanagan, Lyn S PilowskyAbstract:OBJECTIVE: Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D2-like receptors with modest striatal D2 receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D2/D3 dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors’ goal was to evaluate whether treatment with amisulpride results in “limbic selective” D2/D3 receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [123I]Epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of recepto...
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analysis of d2 dopamine receptor occupancy with quantitative spet using the high affinity ligand 123i Epidepride resolving conflicting findings
NeuroImage, 2003Co-Authors: K Erlandsson, Rachel S Mulligan, P J Ell, Lyn S Pilowsky, Rodrigo A Bressan, Vincent J CunninghamAbstract:Abstract Recent studies of limbic cortical dopamine D2 receptor occupancy by clozapine using high-affinity PET and SPET radioligands have produced conflicting findings. It has been suggested that these divergent findings are due to between-study differences in the method used to estimate D2 receptor-binding potential. We compared different methods for estimating striatal and temporal cortical D2 receptor occupancy with high-affinity tracers. In vivo experimental SPET data, obtained with [123I]Epidepride were analysed with reference tissue kinetic modeling and with the ratio method, applied to data corresponding to short (60 min) and long (240 min) acquisition times. Dopamine D2 receptor occupancy by the atypical antipsychotic drug risperidone was evaluated. Simulation experiments were also performed, comparing occupancy values obtained for different receptor densities in relation to different data acquisition times. The simulation results revealed that previously published data regarding errors in occupancy estimation by analysis of time activity data acquired for 60 min cannot be extrapolated to studies performed over 240 min. The ratio method provided accurate temporal cortical D2 receptor occupancy values when applied to data from a late time period, but underestimated the occupancy with earlier data. In striatum, both the late data ratio method and reference tissue kinetic modeling using all data underestimated D2 receptor occupancy. However, more accurate analyses of striatal D2 occupancy still showed selective limbic/cortical occupancy by risperidone. Our results substantiate the previous [123I]Epidepride findings of high temporal cortical occupancy by other atypical antipsychotic drugs and suggest that a potential source of conflicting findings might be short scanning times imposed by [11C]FLB 457, leading to underestimation of temporal cortical D2 receptor occupancy by this method.
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optimizing limbic selective d2 d3 receptor occupancy by risperidone a 123i Epidepride spet study
Journal of Clinical Psychopharmacology, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Lyn S PilowskyAbstract:Selective action at limbic cortical dopamine D2-like receptors is a putative mechanism of atypical antipsychotic efficacy with few extrapyramidal side effects. Although risperidone is an atypical antipsychotic with high affinity for D2 receptors, low-dose risperidone treatment is effective without inducing extrapyramidal symptoms. The objective was to test the hypothesis that treatment with low-dose risperidone results in 'limbic selective' D2/D3 receptor blockade in vivo. Dynamic single photon emission tomography (SPET) sequences were obtained over 5 hours after injection of [123I]-Epidepride (approximately 150 MBq), using a high-resolution triple-headed brain scanner (Marconi Prism 3000XP). Kinetic modelling was performed using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a normal volunteer control group (n = 5). Six patients treated with low-dose risperidone (mean = 2.6 mg) showed moderate levels of D2/D3 occupancy in striatum (49.9%), but higher levels of D2/D3 occupancy in thalamus (70.8%) and temporal cortex (75.2%). Occupancy values in striatum were significantly different from thalamus (F (1,4) = 26.3, p < 0.01) and from temporal cortex (F (1,4) = 53.4, p < 0.01). This is the first study to evaluate striatal and extrastriatal occupancy of risperidone. Low dose treatment with risperidone achieves a similar selectivity of limbic cortical over striatal D2/D3 receptor blockade to that of atypical antipsychotics with lower D2/D3 affinity such as clozapine, olanzapine and quetiapine. This finding is consistent with the relevance of 'limbic selective' D2/D3 receptor occupancy to the therapeutic efficacy of atypical antipsychotic drugs.
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striatal and extra striatal d 2 d 3 dopamine receptor occupancy by quetiapine in vivo 123 i Epidepride single photon emission tomography spet study
British Journal of Psychiatry, 2000Co-Authors: Caroline Stephenson, V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, H M Jones, Lyn S PilowskyAbstract:Background Selective action at limbic cortical dopamine D2-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects. Aims To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo . Method The high-affinity D2/D3 ligand [123I]-Epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients ( n =6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared. Results Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than typical antipsychotics. Conclusions Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for atypical drug action.
Rachel S Mulligan - One of the best experts on this subject based on the ideXlab platform.
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is regionally selective d2 d3 dopamine occupancy sufficient for atypical antipsychotic effect an in vivo quantitative 123i Epidepride spet study of amisulpride treated patients
American Journal of Psychiatry, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Robert J Flanagan, Lyn S PilowskyAbstract:OBJECTIVE: Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D2-like receptors with modest striatal D2 receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D2/D3 dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors’ goal was to evaluate whether treatment with amisulpride results in “limbic selective” D2/D3 receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [123I]Epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of recepto...
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analysis of d2 dopamine receptor occupancy with quantitative spet using the high affinity ligand 123i Epidepride resolving conflicting findings
NeuroImage, 2003Co-Authors: K Erlandsson, Rachel S Mulligan, P J Ell, Lyn S Pilowsky, Rodrigo A Bressan, Vincent J CunninghamAbstract:Abstract Recent studies of limbic cortical dopamine D2 receptor occupancy by clozapine using high-affinity PET and SPET radioligands have produced conflicting findings. It has been suggested that these divergent findings are due to between-study differences in the method used to estimate D2 receptor-binding potential. We compared different methods for estimating striatal and temporal cortical D2 receptor occupancy with high-affinity tracers. In vivo experimental SPET data, obtained with [123I]Epidepride were analysed with reference tissue kinetic modeling and with the ratio method, applied to data corresponding to short (60 min) and long (240 min) acquisition times. Dopamine D2 receptor occupancy by the atypical antipsychotic drug risperidone was evaluated. Simulation experiments were also performed, comparing occupancy values obtained for different receptor densities in relation to different data acquisition times. The simulation results revealed that previously published data regarding errors in occupancy estimation by analysis of time activity data acquired for 60 min cannot be extrapolated to studies performed over 240 min. The ratio method provided accurate temporal cortical D2 receptor occupancy values when applied to data from a late time period, but underestimated the occupancy with earlier data. In striatum, both the late data ratio method and reference tissue kinetic modeling using all data underestimated D2 receptor occupancy. However, more accurate analyses of striatal D2 occupancy still showed selective limbic/cortical occupancy by risperidone. Our results substantiate the previous [123I]Epidepride findings of high temporal cortical occupancy by other atypical antipsychotic drugs and suggest that a potential source of conflicting findings might be short scanning times imposed by [11C]FLB 457, leading to underestimation of temporal cortical D2 receptor occupancy by this method.
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optimizing limbic selective d2 d3 receptor occupancy by risperidone a 123i Epidepride spet study
Journal of Clinical Psychopharmacology, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Lyn S PilowskyAbstract:Selective action at limbic cortical dopamine D2-like receptors is a putative mechanism of atypical antipsychotic efficacy with few extrapyramidal side effects. Although risperidone is an atypical antipsychotic with high affinity for D2 receptors, low-dose risperidone treatment is effective without inducing extrapyramidal symptoms. The objective was to test the hypothesis that treatment with low-dose risperidone results in 'limbic selective' D2/D3 receptor blockade in vivo. Dynamic single photon emission tomography (SPET) sequences were obtained over 5 hours after injection of [123I]-Epidepride (approximately 150 MBq), using a high-resolution triple-headed brain scanner (Marconi Prism 3000XP). Kinetic modelling was performed using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a normal volunteer control group (n = 5). Six patients treated with low-dose risperidone (mean = 2.6 mg) showed moderate levels of D2/D3 occupancy in striatum (49.9%), but higher levels of D2/D3 occupancy in thalamus (70.8%) and temporal cortex (75.2%). Occupancy values in striatum were significantly different from thalamus (F (1,4) = 26.3, p < 0.01) and from temporal cortex (F (1,4) = 53.4, p < 0.01). This is the first study to evaluate striatal and extrastriatal occupancy of risperidone. Low dose treatment with risperidone achieves a similar selectivity of limbic cortical over striatal D2/D3 receptor blockade to that of atypical antipsychotics with lower D2/D3 affinity such as clozapine, olanzapine and quetiapine. This finding is consistent with the relevance of 'limbic selective' D2/D3 receptor occupancy to the therapeutic efficacy of atypical antipsychotic drugs.
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striatal and extra striatal d 2 d 3 dopamine receptor occupancy by quetiapine in vivo 123 i Epidepride single photon emission tomography spet study
British Journal of Psychiatry, 2000Co-Authors: Caroline Stephenson, V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, H M Jones, Lyn S PilowskyAbstract:Background Selective action at limbic cortical dopamine D2-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects. Aims To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo . Method The high-affinity D2/D3 ligand [123I]-Epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients ( n =6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared. Results Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than typical antipsychotics. Conclusions Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for atypical drug action.
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striatal and temporal cortical d2 d3 receptor occupancy by olanzapine and sertindole in vivo a 123i Epidepride single photon emission tomography spet study
Psychopharmacology, 2000Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, R I Ohlsen, V W Pike, P J Ell, Sveto Gacinovic, R W Kerwin, Lyn S PilowskyAbstract:Rationale: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. Objectives: To test the hypothesis that olanzapine, a novel atypical antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. Methods: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]Epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide) and single photon emission tomography (SPET). An estimate of [123I]Epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving typical antipsychotic drugs (n=12) and clozapine (n=10). Results: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with typical antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all antipsychotic drugs studied. Conclusions: The atypical antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their atypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of atypical antipsychotic drugs.
V Bigliani - One of the best experts on this subject based on the ideXlab platform.
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striatal and extra striatal d 2 d 3 dopamine receptor occupancy by quetiapine in vivo 123 i Epidepride single photon emission tomography spet study
British Journal of Psychiatry, 2000Co-Authors: Caroline Stephenson, V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, H M Jones, Lyn S PilowskyAbstract:Background Selective action at limbic cortical dopamine D2-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects. Aims To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo . Method The high-affinity D2/D3 ligand [123I]-Epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients ( n =6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared. Results Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than typical antipsychotics. Conclusions Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for atypical drug action.
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striatal and temporal cortical d2 d3 receptor occupancy by olanzapine and sertindole in vivo a 123i Epidepride single photon emission tomography spet study
Psychopharmacology, 2000Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, R I Ohlsen, V W Pike, P J Ell, Sveto Gacinovic, R W Kerwin, Lyn S PilowskyAbstract:Rationale: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. Objectives: To test the hypothesis that olanzapine, a novel atypical antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. Methods: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]Epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide) and single photon emission tomography (SPET). An estimate of [123I]Epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving typical antipsychotic drugs (n=12) and clozapine (n=10). Results: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with typical antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all antipsychotic drugs studied. Conclusions: The atypical antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their atypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of atypical antipsychotic drugs.
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in vivo occupancy of striatal and temporal cortical d2 d3 dopamine receptors by typical antipsychotic drugs 123i Epidepride single photon emission tomography spet study
British Journal of Psychiatry, 1999Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, Caroline Stephenson, Lyn S PilowskyAbstract:BACKGROUND The dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade. AIM To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-Epidepride. METHOD [123I]-Epidepride SPET scans were performed on 12 patients with schizophrenia treated with antipsychotics and II age-matched healthy controls. [123I]-Epidepride 'specific binding' to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined. RESULTS Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively. CONCLUSIONS Typical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.
Christer Halldin - One of the best experts on this subject based on the ideXlab platform.
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dopamine d2 receptor quantification in extrastriatal brain regions using 123i Epidepride with bolus infusion
Synapse, 2000Co-Authors: Lars H Pinborg, Christer Halldin, Carlgunnar Swahn, Charlotte Videbaek, Gitte M Knudsen, L Friberg, Olaf B Paulson, N A LassenAbstract:The iodinated benzamide Epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]Epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions.
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metabolism of 123i Epidepride may affect brain dopamine d2 receptor imaging with single photon emission tomography
European Journal of Nuclear Medicine and Molecular Imaging, 2000Co-Authors: Kim A Bergstrom, Christer Halldin, Jyrki T Kuikka, Kari Akerman, Jukka Hiltunen, Johannes Lehtonen, Jari TiihonenAbstract:Iodine-123 labelled Epidepride is a novel radiopharmaceutical for the study of cerebral dopamine D2 receptors using single-photon emission tomography (SPET). A lipophilic labelled metabolite of [123I]Epidepride which may enter the brain and hamper the quantitation of receptors has been observed in human plasma. In the present study, gradient high-performance liquid chromatography (HPLC) was used to investigate the plasma concentration of the lipophilic labelled metabolite and its correlation to SPET imaging of striatal dopamine D2 receptors. A linear regression fit showed a negative correlation between the amount of the lipophilic labelled metabolite and the striatum to cerebellum ratio (n=16, R=–0.58, P<0.02), suggesting that plasma metabolite analysis is essential when imaging dopamine D2 receptors with SPET using [123I]Epidepride.
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carbon 11 Epidepride a suitable radioligand for pet investigation of striatal and extrastriatal dopamine d2 receptors
Nuclear Medicine and Biology, 1999Co-Authors: Oliver Langer, Hakan Hall, Christer Halldin, F Dolle, Carlgunnar Swahn, Hans Olsson, Per Karlsson, Johan Sandell, Camilla Lundkvist, Francoise VaufreyAbstract:Epidepride [(S)-(-)-N-([1-ethyl-2-pyrrolidinyl]methyl)-5-iodo-2,3-dimethoxybenza mide] binds with a picomolar affinity (Ki = 24 pM) to the dopamine D2 receptor. Iodine-123-labeled Epidepride has been used previously to study striatal and extrastriatal dopamine D2 receptors with single photon emission computed tomography (SPECT). Our aim was to label Epidepride with carbon-11 for comparative quantitative studies between positron emission tomography (PET) and SPECT. Epidepride was synthesized from its bromo-analogue FLB 457 via the corresponding trimethyl-tin derivative. In an alternative synthetic pathway, the corresponding substituted benzoic acid was reacted with the optically pure aminomethylpyrrolidine-derivative. Demethylation of Epidepride gave the desmethyl-derivative, which was reacted with [11C]methyl triflate. Total radiochemical yield was 40-50% within a total synthesis time of 30 min. The specific radioactivity at the end of synthesis was 37-111 GBq/micromol (1,000-3,000 Ci/mmol). Human postmortem whole-hemisphere autoradiography demonstrated dense binding in the caudate putamen, and also in extrastriatal areas such as the thalamus and the neocortex. The binding was inhibited by unlabeled raclopride. PET studies in a cynomolgus monkey demonstrated high uptake in the striatum and in several extrastriatal regions. At 90 min after injection, uptake in the striatum, thalamus and neocortex was about 11, 4, and 2 times higher than in the cerebellum, respectively. Pretreatment experiment with unlabeled raclopride (1 mg/kg) inhibited 50-70% of [11C]Epidepride binding. The fraction of unchanged [11C]Epidepride in monkey plasma determined by a gradient high performance liquid chromatography (HPLC) method was about 30% of the total radioactivity at 30 min after injection of [11C]Epidepride. The availability of [11C]Epidepride allows the PET-verification of the data obtained from quantitation studies with SPECT.
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autoradiographic comparison of 125i Epidepride and 125i ncq 298 binding to human brain extrastriated dopamine receptors
Nuclear Medicine and Biology, 1997Co-Authors: Hakan Hall, Lars Farde, Christer Halldin, Eva Jerning, Marie K Osterlund, Goran SedvallAbstract:Abstract Extrastriatal d 2 -dopamine receptors can be visualized in the monkey and human brain using the benzamides [ 11 C]- and [ 76 Br]FLB 457 in PET and [ 123 I]Epidepride in SPECT but not with the salicylamide analogues [ 76 Br]FLB 463 and [ 123 I]NCQ 298. To clarify the background for the differences in binding seen in vivo , we have compared the in vitro binding of [ 125 I]Epidepride and [ 125 I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors.
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Striatal and extrastriatal imaging of dopamine D2 receptors in the living human brain with [123I]Epidepride single-photon emission tomography
European journal of nuclear medicine, 1997Co-Authors: Jyrki T Kuikka, Christer Halldin, Kim A Bergstrom, Kari Akerman, Jukka Hiltunen, Pirkko Räsänen, Esko Vanninen, Jari TiihonenAbstract:The iodine-123 labelled ligand benzamide Epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D2 receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91±0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45–60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [123I]Epidepride can be used for imaging striatal and extrastriatal dopamine D2 receptor sites in the living human brain.