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Sami S Zoghbi - One of the best experts on this subject based on the ideXlab platform.
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123i Iomazenil spect benzodiazepine receptor imaging in schizophrenia
Psychiatry Research-neuroimaging, 1999Co-Authors: Nicolaas Paul L G Verhoeff, Sami S Zoghbi, John Seibyl, Masahiro Fujita, Anissa Abidargham, Nallakkandi Rajeevan, Jair C Soares, Cyril Dsouza, Kathleen Degen, John H KrystalAbstract:Abstract Deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia based on postmortem studies. However, in vivo studies have shown predominantly negative or conflicting results. The goal of this study was to better characterize possible changes of the regional GABA A -benzodiazepine receptor distribution volume (BZR V 3 -p) in schizophrenia in vivo, using a larger sample size than previous studies. Single photon emission computed tomography (SPECT) with [ 123 I]Iomazenil was used with a constant infusion paradigm to measure the BZR V 3 -p under sustained radiotracer equilibrium conditions. Twenty-five patients with schizophrenia and 24 matched healthy control subjects were studied. Positive and Negative Syndrome Scale (PANSS) ratings were done in all subjects. Statistical parametric mapping (SPM) 96 was used to compare patients and control subjects as well as to study the relationship between SPECT results and composite PANSS scores based on two factorial models: the pentagonal model (positive, negative, dysphoric mood, activation, and autistic preoccupation factors) and the taxometric model (disorganized dimension). On the basis of ‘absolute' values of V 3 -p with no normalization for total brain uptake, the schizophrenic patients showed no signficant differences in BZR levels compared to the healthy control subjects. With a global normalization procedure, which is more sensitive to relative regional differences in activity, BZR V 3 -p was significantly decreased in the patients in the left precentral gyrus (BA 6). The relative BZR V 3 -p showed a significant positive correlation with duration of illness in the superior occipital gyri (BA 19). No significant correlations were observed between either absolute or relative BZR V 3 -p and either age or any of the composite PANSS scores based on any of the two factorial models in either patients or control subjects. No significant differences were observed between cigarette smoking vs. non-smoking patients, nor between the patients on atypical antipsychotics vs. on typical antipsychotics vs. not on any antipsychotics. In general, no significant differences in BZR V 3 -p were observed between patients and control subjects, except for a decrease in relative BZR V 3 -p in the left precentral gyrus. Grey matter atrophy is unlikely to be the cause for this decrease. However, we could not exclude that possibility. The positive correlation with duration of illness might reflect the relative preservation of neurons expressing BZR in the superior occipital gyri as compared to other cortical brain regions in schizophrenia.
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effects of vigabatrin on the gabaergic system as determined by 123i Iomazenil spect and gaba mrs
Epilepsia, 1999Co-Authors: Nicolaas Paul L G Verhoeff, Sami S Zoghbi, John Seibyl, Masahiro Fujita, Ognen A C Petroff, Fahmeed Hyder, Nallakkandi Rajeevan, Douglas L Rothman, Richard H Mattson, Robert B. InnisAbstract:Summary: Purpose: To evaluate effects of vigabatrin (VGB) by using [123I]Iomazenil single-photon emission computed tomography (SPECT) to estimate central γ-aminobutyric acid (GABAA)/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. Methods: Six patients with partial seizures had both SPECT and MRS before and 25–84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 × 2 × 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]Iomazenil concentration to estimate BZR distribution volume (VT-p and V'T, respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR VT-p or V'T. SPM96 (either no global normalization or proportional scaling) was used to compare BZR VT-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. Results: Occipital GABA levels were increased threefold (without VGB, 1.1 ± 0.1μmol/g; with VGB, 2.9 ± 0.5 μmol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either VT-p (without VGB, 6.00 ± 0.91 ml/g; with VGB, 5.86 ± 0.44 ml/g; p = 0.92) or V'T (without VGB, 41.1 ± 11.2 ml/g; with VGB, 41.2 ± 9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. Conclusions: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.
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quantitation of benzodiazepine receptor binding with pet 11c Iomazenil and spect 123i Iomazenil preliminary results of a direct comparison in healthy human subjects
Psychiatry Research-neuroimaging, 1999Co-Authors: Douglas J Bremner, Sami S Zoghbi, Ronald M Baldwin, John Seibyl, Yolanda Zeaponce, Andrew G Horti, Chin K Ng, Robert Soufer, Lawrence H Staib, Dennis S CharneyAbstract:Abstract Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [ 11 C]Iomazenil and [ 123 I]Iomazenil, respectively. All subjects were administered a single bolus of high specific activity Iomazenil labeled with 11 C or 123 I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP= B max / K d ) and product of BP and the fraction of free non-protein-bound parent compound (V3′). Mean values for V3′ in PET and SPECT were as follows: temporal cortex 23±5 and 22±3 ml/g, frontal cortex 23±6 and 22±3 ml/g, occipital cortex 28±3 and 31±5 ml/g, and striatum 4±4 and 7±4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.
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clinical research effects of vigabatrin on the gabaergic system as determined by 231 Iomazenil spect and gaba mrs
1999Co-Authors: Nicolaas Paul, Sami S Zoghbi, John Seibyl, Masahiro Fujita, Ognen A C Petroff, Fahmeed Hyder, Douglas L Rothman, Richard H Mattson, L G Verhoeff, R B InnisAbstract:Summary: Purpose: To evaluate effects of vigabatrin (VGB) by using [1231)Iomazenil single-photon emission computed tomography (SPECT) to estimate central y-aminobutyric acid (GABA,)/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. Methods: Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g P.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T,-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [1231]Iomazenil concentration to estimate BZR distribution volume (V,-p and Vk, respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V,-p or V;. SPM96 (either no global normalization or proportional scaling) was used to compare BZR V,-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. Results: Occipital GABA levels were increased threefold (without VGB, 1.1 -t 0.1 pmol/g; with VGB, 2.9 & 0.5 pmol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V,-p (without VGB, 6.00 2 0.91 mllg; with VGB, 5.86 k 0.44 ml/g; p = 0.92) or V; (without VGB, 41.1 2 11.2 ml/g; with VGB, 41.2 _t 9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. Conclusions: A clinically effective dose of VGB caused a
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alterations of benzodiazepine receptors in type ii alcoholic subjects measured with spect and 123i Iomazenil
American Journal of Psychiatry, 1998Co-Authors: Anissa Abidargham, Sami S Zoghbi, Ronald M Baldwin, Nallakkandi Rajeevan, John H Krystal, S Anjilvel, Barbara Ellen Scanley, Steven P Ellis, Ismene L Petrakis, John SeibylAbstract:Objective:Alterations in cortical benzodiazepine receptor density have been described in postmortem and in vivo studies of alcoholic subjects. The authors attempted to replicate these findings using single photon emission computed tomography and the benzodiazepine receptor radiotracer [123I]Iomazenil. Method:They measured the distribution volume of benzodiazepine receptors in 11 recently detoxified patients with type II alcoholism and 11 healthy comparison subjects. The tracer was given as a bolus followed by a continuous infusion to achieve sustained binding equilibrium at the benzodiazepine receptors. Data were analyzed by using a region of interest method (regions of interest were identified on coregistered magnetic resonance imaging scans) and by a pixel-by-pixel method (distribution volume maps were analyzed with statistical parametric mapping for between-group differences).Results:The region of interest analysis revealed that alcoholic patients had significantly lower benzodiazepine distribution vol...
Ronald M Baldwin - One of the best experts on this subject based on the ideXlab platform.
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kinetic modeling of benzodiazepine receptor binding with pet and high specific activity 11c Iomazenil in healthy human subjects
Synapse, 2000Co-Authors: Douglas J Bremner, Yolanda Zeaponce, Dennis S Charney, Andrew G Horti, Robert Soufer, Lawrence H Staib, Ronald M BaldwinAbstract:Quantitation of the PET benzodiazepine receptor antagonist, ( 11 C)Ioma- zenil, using low specific activity radioligand was recently described. The purpose of this study was to quantitate benzodiazepine receptor binding in human subjects using PET and high specific activity ( 11 C)Iomazenil. Six healthy human subjects underwent PET imaging following a bolus injection of high specific activity (.100 Ci/mmol) ( 11 C)iomaze- nil. Arterial samples were collected at multiple time points after injection for measure- ment of unmetabolized total and nonprotein-bound parent compound in plasma. Time activity curves of radioligand concentration in brain and plasma were analyzed using two and three compartment model. Kinetic rate constants of transfer of radioligand between plasma, nonspecifically bound brain tissue, and specifically bound brain tissue compart- ments were fitted to the model. Values for fitted kinetic rate constants were used in the calculation of measures of benzodiazepine receptor binding, including binding potential (the ratio of receptor density to affinity), and product of BP and the fraction of free nonprotein-bound parent compound (V38). Use of the three compartment model improved the goodness of fit in comparison to the two compartment model. Values for kinetic rate constants and measures of benzodiazepine receptor binding, including BP and V38, were similar to results obtained with the SPECT radioligand ( 123 I)Iomazenil, and a prior report with low specific activity ( 11 C)Iomazenil. Kinetic modeling using the three compartment model with PET and high specific activity ( 11 C)Iomazenil provides a reliable measure of benzodiazepine receptor binding. Synapse 35:68-77, 2000.
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quantitation of benzodiazepine receptor binding with pet 11c Iomazenil and spect 123i Iomazenil preliminary results of a direct comparison in healthy human subjects
Psychiatry Research-neuroimaging, 1999Co-Authors: Douglas J Bremner, Sami S Zoghbi, Ronald M Baldwin, John Seibyl, Yolanda Zeaponce, Andrew G Horti, Chin K Ng, Robert Soufer, Lawrence H Staib, Dennis S CharneyAbstract:Abstract Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [ 11 C]Iomazenil and [ 123 I]Iomazenil, respectively. All subjects were administered a single bolus of high specific activity Iomazenil labeled with 11 C or 123 I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP= B max / K d ) and product of BP and the fraction of free non-protein-bound parent compound (V3′). Mean values for V3′ in PET and SPECT were as follows: temporal cortex 23±5 and 22±3 ml/g, frontal cortex 23±6 and 22±3 ml/g, occipital cortex 28±3 and 31±5 ml/g, and striatum 4±4 and 7±4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.
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alterations of benzodiazepine receptors in type ii alcoholic subjects measured with spect and 123i Iomazenil
American Journal of Psychiatry, 1998Co-Authors: Anissa Abidargham, Sami S Zoghbi, Ronald M Baldwin, Nallakkandi Rajeevan, John H Krystal, S Anjilvel, Barbara Ellen Scanley, Steven P Ellis, Ismene L Petrakis, John SeibylAbstract:Objective:Alterations in cortical benzodiazepine receptor density have been described in postmortem and in vivo studies of alcoholic subjects. The authors attempted to replicate these findings using single photon emission computed tomography and the benzodiazepine receptor radiotracer [123I]Iomazenil. Method:They measured the distribution volume of benzodiazepine receptors in 11 recently detoxified patients with type II alcoholism and 11 healthy comparison subjects. The tracer was given as a bolus followed by a continuous infusion to achieve sustained binding equilibrium at the benzodiazepine receptors. Data were analyzed by using a region of interest method (regions of interest were identified on coregistered magnetic resonance imaging scans) and by a pixel-by-pixel method (distribution volume maps were analyzed with statistical parametric mapping for between-group differences).Results:The region of interest analysis revealed that alcoholic patients had significantly lower benzodiazepine distribution vol...
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synthesis and pet imaging of the benzodiazepine receptor tracer n methyl 11c Iomazenil
Nuclear Medicine and Biology, 1995Co-Authors: Ronald M Baldwin, Yolanda Zeaponce, Andrew G Horti, Douglas J Bremner, Morgan D Stratton, Robert F Dannals, Hayden T Ravert, Chin K Ng, Robert Soufer, Dennis S CharneyAbstract:Abstract The central benzodiazepine receptor tracer [ N -methyl- 11 C]Iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor norIomazenil with [ 11 C]methyl iodide. The [ 11 C]CH 3 I (prepared by reduction of [ 11 C]CO 2 with LiAlH 4 followed by reaction with HI) was reacted with norIomazenil in N,N -dimethylformamide and Bu 4 N + OH − for 1 min at 80 °C and purified by HPLC (C 18 , 34% CH 3 CN/H 2 O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [ 11 C]Iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [ 11 C]flumazenil PET and [ 123 I]Iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [ 11 C]Iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.
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reproducibility of spect measurement of benzodiazepine receptors in human brain with iodine 123 Iomazenil
The Journal of Nuclear Medicine, 1995Co-Authors: Anissa Abidargham, Sami S Zoghbi, Ronald M Baldwin, Yolanda Zeaponce, Marc Laruelle, Dennis S Charney, Paul B Hoffer, Mitchell S Gandelman, Penny Randall, Robert B. InnisAbstract:UNLABELLED: Iodine-123-Iomazenil is a SPECT radiotracer used to image and quantify benzodiazepine receptors. The reproducibility of the measurement of benzodiazepine receptors in human brain with [123I]Iomazenil and SPECT was investigated with a test/retest paradigm. METHODS: Six subjects underwent two experiments during a 1-wk interval. Iodine-123-Iomazenil was injected as a single bolus (12 mCi). The time-activity curves of the tracer in the arterial plasma were measured and corrected for metabolites. Regional time-activity curves of five brain regions were measured with the CERASPECT camera for 145 min postinjection with serial 2-min acquisitions. Data were analyzed using three kinetic models that included a two-compartment model, an unconstrained three-compartment model and a three-compartment model with a constraint on the nondisplaceable compartment. RESULTS: The results from the various analyses and fitting strategies were compared. The variability (average absolute difference between test and retest, expressed as a percentage of the mean of both measurements) was 10% to 17%, depending on the outcome measure and the fitting procedure. The most reproducible outcome measure was the regional tracer distribution volume relative to the total arterial concentration (VT'). VT' showed an average regional variability of 10% +/- 2%, with an intraclass correlation coefficient of 0.81. CONCLUSION: SPECT measurement of regional [123I]Iomazenil VT' is reproducible and reliable. The use of regional ratios results in a significant loss of information.
John Seibyl - One of the best experts on this subject based on the ideXlab platform.
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probing gaba receptor function in schizophrenia with Iomazenil
Neuropsychopharmacology, 2011Co-Authors: John Seibyl, Richard Andrew Sewell, Deepak Cyril DsouzaAbstract:Several lines of evidence from post-mortem, brain imaging, and genetic studies in schizophrenia patients suggest that Gamma-amino butyric acid (GABA) deficits may contribute to the pathophysiology of schizophrenia. Pharmacological induction of a transient GABA-deficit state has been shown to enhance vulnerability of healthy subjects to the psychotomimetic effects of various drugs. Exacerbating or creating a GABA deficit was hypothesized to induce or unmask psychosis in schizophrenia patients, but not in healthy controls. To test this hypothesis, a transient GABA deficit was pharmacologically induced in schizophrenia patients and healthy controls using Iomazenil, an antagonist and partial inverse agonist of the benzodiazepine receptor. In a double-blind, randomized, placebo-controlled study, clinically stable chronic schizophrenia patients (n=13) received Iomazenil (3.7 μg administered intravenously over 10 min). Psychosis was measured using the Brief Psychiatric Rating Scale and perceptual alterations were measured using the Clinician Administered Dissociative Symptoms Scale before and after Iomazenil administration. These data were compared with the effects of Iomazenil in healthy subjects (n=20). Iomazenil produced increases in psychotic symptoms and perceptual alterations in schizophrenia patients, but not in healthy controls. The greater vulnerability of schizophrenia patients to the effects of Iomazenil relative to controls provides further support for the GABA-deficit hypothesis of schizophrenia.
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123i Iomazenil spect benzodiazepine receptor imaging in schizophrenia
Psychiatry Research-neuroimaging, 1999Co-Authors: Nicolaas Paul L G Verhoeff, Sami S Zoghbi, John Seibyl, Masahiro Fujita, Anissa Abidargham, Nallakkandi Rajeevan, Jair C Soares, Cyril Dsouza, Kathleen Degen, John H KrystalAbstract:Abstract Deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia based on postmortem studies. However, in vivo studies have shown predominantly negative or conflicting results. The goal of this study was to better characterize possible changes of the regional GABA A -benzodiazepine receptor distribution volume (BZR V 3 -p) in schizophrenia in vivo, using a larger sample size than previous studies. Single photon emission computed tomography (SPECT) with [ 123 I]Iomazenil was used with a constant infusion paradigm to measure the BZR V 3 -p under sustained radiotracer equilibrium conditions. Twenty-five patients with schizophrenia and 24 matched healthy control subjects were studied. Positive and Negative Syndrome Scale (PANSS) ratings were done in all subjects. Statistical parametric mapping (SPM) 96 was used to compare patients and control subjects as well as to study the relationship between SPECT results and composite PANSS scores based on two factorial models: the pentagonal model (positive, negative, dysphoric mood, activation, and autistic preoccupation factors) and the taxometric model (disorganized dimension). On the basis of ‘absolute' values of V 3 -p with no normalization for total brain uptake, the schizophrenic patients showed no signficant differences in BZR levels compared to the healthy control subjects. With a global normalization procedure, which is more sensitive to relative regional differences in activity, BZR V 3 -p was significantly decreased in the patients in the left precentral gyrus (BA 6). The relative BZR V 3 -p showed a significant positive correlation with duration of illness in the superior occipital gyri (BA 19). No significant correlations were observed between either absolute or relative BZR V 3 -p and either age or any of the composite PANSS scores based on any of the two factorial models in either patients or control subjects. No significant differences were observed between cigarette smoking vs. non-smoking patients, nor between the patients on atypical antipsychotics vs. on typical antipsychotics vs. not on any antipsychotics. In general, no significant differences in BZR V 3 -p were observed between patients and control subjects, except for a decrease in relative BZR V 3 -p in the left precentral gyrus. Grey matter atrophy is unlikely to be the cause for this decrease. However, we could not exclude that possibility. The positive correlation with duration of illness might reflect the relative preservation of neurons expressing BZR in the superior occipital gyri as compared to other cortical brain regions in schizophrenia.
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effects of vigabatrin on the gabaergic system as determined by 123i Iomazenil spect and gaba mrs
Epilepsia, 1999Co-Authors: Nicolaas Paul L G Verhoeff, Sami S Zoghbi, John Seibyl, Masahiro Fujita, Ognen A C Petroff, Fahmeed Hyder, Nallakkandi Rajeevan, Douglas L Rothman, Richard H Mattson, Robert B. InnisAbstract:Summary: Purpose: To evaluate effects of vigabatrin (VGB) by using [123I]Iomazenil single-photon emission computed tomography (SPECT) to estimate central γ-aminobutyric acid (GABAA)/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. Methods: Six patients with partial seizures had both SPECT and MRS before and 25–84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 × 2 × 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]Iomazenil concentration to estimate BZR distribution volume (VT-p and V'T, respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR VT-p or V'T. SPM96 (either no global normalization or proportional scaling) was used to compare BZR VT-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. Results: Occipital GABA levels were increased threefold (without VGB, 1.1 ± 0.1μmol/g; with VGB, 2.9 ± 0.5 μmol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either VT-p (without VGB, 6.00 ± 0.91 ml/g; with VGB, 5.86 ± 0.44 ml/g; p = 0.92) or V'T (without VGB, 41.1 ± 11.2 ml/g; with VGB, 41.2 ± 9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. Conclusions: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.
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quantitation of benzodiazepine receptor binding with pet 11c Iomazenil and spect 123i Iomazenil preliminary results of a direct comparison in healthy human subjects
Psychiatry Research-neuroimaging, 1999Co-Authors: Douglas J Bremner, Sami S Zoghbi, Ronald M Baldwin, John Seibyl, Yolanda Zeaponce, Andrew G Horti, Chin K Ng, Robert Soufer, Lawrence H Staib, Dennis S CharneyAbstract:Abstract Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [ 11 C]Iomazenil and [ 123 I]Iomazenil, respectively. All subjects were administered a single bolus of high specific activity Iomazenil labeled with 11 C or 123 I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP= B max / K d ) and product of BP and the fraction of free non-protein-bound parent compound (V3′). Mean values for V3′ in PET and SPECT were as follows: temporal cortex 23±5 and 22±3 ml/g, frontal cortex 23±6 and 22±3 ml/g, occipital cortex 28±3 and 31±5 ml/g, and striatum 4±4 and 7±4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.
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clinical research effects of vigabatrin on the gabaergic system as determined by 231 Iomazenil spect and gaba mrs
1999Co-Authors: Nicolaas Paul, Sami S Zoghbi, John Seibyl, Masahiro Fujita, Ognen A C Petroff, Fahmeed Hyder, Douglas L Rothman, Richard H Mattson, L G Verhoeff, R B InnisAbstract:Summary: Purpose: To evaluate effects of vigabatrin (VGB) by using [1231)Iomazenil single-photon emission computed tomography (SPECT) to estimate central y-aminobutyric acid (GABA,)/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. Methods: Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g P.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T,-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [1231]Iomazenil concentration to estimate BZR distribution volume (V,-p and Vk, respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V,-p or V;. SPM96 (either no global normalization or proportional scaling) was used to compare BZR V,-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. Results: Occipital GABA levels were increased threefold (without VGB, 1.1 -t 0.1 pmol/g; with VGB, 2.9 & 0.5 pmol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V,-p (without VGB, 6.00 2 0.91 mllg; with VGB, 5.86 k 0.44 ml/g; p = 0.92) or V; (without VGB, 41.1 2 11.2 ml/g; with VGB, 41.2 _t 9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. Conclusions: A clinically effective dose of VGB caused a
Robert B. Innis - One of the best experts on this subject based on the ideXlab platform.
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effects of vigabatrin on the gabaergic system as determined by 123i Iomazenil spect and gaba mrs
Epilepsia, 1999Co-Authors: Nicolaas Paul L G Verhoeff, Sami S Zoghbi, John Seibyl, Masahiro Fujita, Ognen A C Petroff, Fahmeed Hyder, Nallakkandi Rajeevan, Douglas L Rothman, Richard H Mattson, Robert B. InnisAbstract:Summary: Purpose: To evaluate effects of vigabatrin (VGB) by using [123I]Iomazenil single-photon emission computed tomography (SPECT) to estimate central γ-aminobutyric acid (GABAA)/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. Methods: Six patients with partial seizures had both SPECT and MRS before and 25–84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 × 2 × 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]Iomazenil concentration to estimate BZR distribution volume (VT-p and V'T, respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR VT-p or V'T. SPM96 (either no global normalization or proportional scaling) was used to compare BZR VT-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. Results: Occipital GABA levels were increased threefold (without VGB, 1.1 ± 0.1μmol/g; with VGB, 2.9 ± 0.5 μmol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either VT-p (without VGB, 6.00 ± 0.91 ml/g; with VGB, 5.86 ± 0.44 ml/g; p = 0.92) or V'T (without VGB, 41.1 ± 11.2 ml/g; with VGB, 41.2 ± 9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. Conclusions: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.
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reproducibility of spect measurement of benzodiazepine receptors in human brain with iodine 123 Iomazenil
The Journal of Nuclear Medicine, 1995Co-Authors: Anissa Abidargham, Sami S Zoghbi, Ronald M Baldwin, Yolanda Zeaponce, Marc Laruelle, Dennis S Charney, Paul B Hoffer, Mitchell S Gandelman, Penny Randall, Robert B. InnisAbstract:UNLABELLED: Iodine-123-Iomazenil is a SPECT radiotracer used to image and quantify benzodiazepine receptors. The reproducibility of the measurement of benzodiazepine receptors in human brain with [123I]Iomazenil and SPECT was investigated with a test/retest paradigm. METHODS: Six subjects underwent two experiments during a 1-wk interval. Iodine-123-Iomazenil was injected as a single bolus (12 mCi). The time-activity curves of the tracer in the arterial plasma were measured and corrected for metabolites. Regional time-activity curves of five brain regions were measured with the CERASPECT camera for 145 min postinjection with serial 2-min acquisitions. Data were analyzed using three kinetic models that included a two-compartment model, an unconstrained three-compartment model and a three-compartment model with a constraint on the nondisplaceable compartment. RESULTS: The results from the various analyses and fitting strategies were compared. The variability (average absolute difference between test and retest, expressed as a percentage of the mean of both measurements) was 10% to 17%, depending on the outcome measure and the fitting procedure. The most reproducible outcome measure was the regional tracer distribution volume relative to the total arterial concentration (VT'). VT' showed an average regional variability of 10% +/- 2%, with an intraclass correlation coefficient of 0.81. CONCLUSION: SPECT measurement of regional [123I]Iomazenil VT' is reproducible and reliable. The use of regional ratios results in a significant loss of information.
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evaluation of ultrafiltration for the free fraction determination of single photon emission computed tomography spect radiotracers β cit ibf and Iomazenil
Journal of Pharmaceutical Sciences, 1994Co-Authors: Mitchell S Gandelman, Sami S Zoghbi, Ronald M Baldwin, Yolanda Zeaponce, Robert B. InnisAbstract:An ultrafiltration system was evaluated for the free‐fraction measurement of SPECT radiotracers (β‐CIT, IBF, and Iomazenil) used in functional brain imaging. The effect of temperature, storage, centrifugal force, tracer concentration, and percentage filtered demonstrated a relative error of < 9%. As a result of the minimal temperature effect, 25 °C was employed for all measurements. A comparison of the ultrafiltration system with equilibrium dialysis revealed < 5% difference for β‐CIT and Iomazenil, but 16% for IBF. Additionally, the time and ease of operation considerably favored the ultrafiltration system. The precision quantitated by repetition was < 6% for between‐run and within‐run variability. In conclusion, ultrafiltration provided rapid results, demonstrated minor analytical errors, revealed generally good correlation with equilibrium dialysis, and allowed excellent precision.
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Evaluation of Ultrafiltration for the Free‐Fraction Determination of Single Photon Emission Computed Tomography (SPECT) Radiotracers: β‐CIT, IBF, and Iomazenil
Journal of Pharmaceutical Sciences, 1994Co-Authors: Mitchell S Gandelman, Sami S Zoghbi, Ronald M Baldwin, Yolanda Zea-ponce, Robert B. InnisAbstract:An ultrafiltration system was evaluated for the free‐fraction measurement of SPECT radiotracers (β‐CIT, IBF, and Iomazenil) used in functional brain imaging. The effect of temperature, storage, centrifugal force, tracer concentration, and percentage filtered demonstrated a relative error of < 9%. As a result of the minimal temperature effect, 25 °C was employed for all measurements. A comparison of the ultrafiltration system with equilibrium dialysis revealed < 5% difference for β‐CIT and Iomazenil, but 16% for IBF. Additionally, the time and ease of operation considerably favored the ultrafiltration system. The precision quantitated by repetition was < 6% for between‐run and within‐run variability. In conclusion, ultrafiltration provided rapid results, demonstrated minor analytical errors, revealed generally good correlation with equilibrium dialysis, and allowed excellent precision.
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spect quantification of 123i Iomazenil binding to benzodiazepine receptors in nonhuman primates ii equilibrium analysis of constant infusion experiments and correlation with in vitro parameters
Journal of Cerebral Blood Flow and Metabolism, 1994Co-Authors: Marc Laruelle, Sami S Zoghbi, Ronald M Baldwin, Mohammed S Altikriti, Yolanda Zeaponce, Dennis S Charney, Paul B Hoffer, Anissa Abidargham, Robert B. InnisAbstract:In vivo benzodiazepine receptor equilibrium dissociation constant, KD, and maximum number of binding sites, Bmax, were measured by single photon emission computerized tomography (SPECT) in three baboons. Animals were injected with a bolus followed by a constant i.v. infusion of the high affinity benzodiazepine ligand [123I]Iomazenil. Plasma steady-state concentration and receptor–ligand equilibrium were reached within 2 and 3 h, respectively, and were sustained for the duration (4–9 h) of the experiments (n = 15). At the end of the experiments, a receptor saturating dose of flumazenil (0.2 mg/kg) was injected to measure nondisplaceable activity. Experiments were carried out at various levels of specific activity, and Scatchard analysis was performed for derivation of the KD (0.59 ± 0.09 nM) and Bmax (from 126 nM in the occipital region to 68 nM in the striatum). Two animals were killed and [125I]Iomazenil Bmax and KD were measured at 22 and 37°C on occipital homogenate membranes. In vitro values of Bmax (...
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kinetic modeling of benzodiazepine receptor binding with pet and high specific activity 11c Iomazenil in healthy human subjects
Synapse, 2000Co-Authors: Douglas J Bremner, Yolanda Zeaponce, Dennis S Charney, Andrew G Horti, Robert Soufer, Lawrence H Staib, Ronald M BaldwinAbstract:Quantitation of the PET benzodiazepine receptor antagonist, ( 11 C)Ioma- zenil, using low specific activity radioligand was recently described. The purpose of this study was to quantitate benzodiazepine receptor binding in human subjects using PET and high specific activity ( 11 C)Iomazenil. Six healthy human subjects underwent PET imaging following a bolus injection of high specific activity (.100 Ci/mmol) ( 11 C)iomaze- nil. Arterial samples were collected at multiple time points after injection for measure- ment of unmetabolized total and nonprotein-bound parent compound in plasma. Time activity curves of radioligand concentration in brain and plasma were analyzed using two and three compartment model. Kinetic rate constants of transfer of radioligand between plasma, nonspecifically bound brain tissue, and specifically bound brain tissue compart- ments were fitted to the model. Values for fitted kinetic rate constants were used in the calculation of measures of benzodiazepine receptor binding, including binding potential (the ratio of receptor density to affinity), and product of BP and the fraction of free nonprotein-bound parent compound (V38). Use of the three compartment model improved the goodness of fit in comparison to the two compartment model. Values for kinetic rate constants and measures of benzodiazepine receptor binding, including BP and V38, were similar to results obtained with the SPECT radioligand ( 123 I)Iomazenil, and a prior report with low specific activity ( 11 C)Iomazenil. Kinetic modeling using the three compartment model with PET and high specific activity ( 11 C)Iomazenil provides a reliable measure of benzodiazepine receptor binding. Synapse 35:68-77, 2000.
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quantitation of benzodiazepine receptor binding with pet 11c Iomazenil and spect 123i Iomazenil preliminary results of a direct comparison in healthy human subjects
Psychiatry Research-neuroimaging, 1999Co-Authors: Douglas J Bremner, Sami S Zoghbi, Ronald M Baldwin, John Seibyl, Yolanda Zeaponce, Andrew G Horti, Chin K Ng, Robert Soufer, Lawrence H Staib, Dennis S CharneyAbstract:Abstract Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [ 11 C]Iomazenil and [ 123 I]Iomazenil, respectively. All subjects were administered a single bolus of high specific activity Iomazenil labeled with 11 C or 123 I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP= B max / K d ) and product of BP and the fraction of free non-protein-bound parent compound (V3′). Mean values for V3′ in PET and SPECT were as follows: temporal cortex 23±5 and 22±3 ml/g, frontal cortex 23±6 and 22±3 ml/g, occipital cortex 28±3 and 31±5 ml/g, and striatum 4±4 and 7±4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.
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synthesis and pet imaging of the benzodiazepine receptor tracer n methyl 11c Iomazenil
Nuclear Medicine and Biology, 1995Co-Authors: Ronald M Baldwin, Yolanda Zeaponce, Andrew G Horti, Douglas J Bremner, Morgan D Stratton, Robert F Dannals, Hayden T Ravert, Chin K Ng, Robert Soufer, Dennis S CharneyAbstract:Abstract The central benzodiazepine receptor tracer [ N -methyl- 11 C]Iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor norIomazenil with [ 11 C]methyl iodide. The [ 11 C]CH 3 I (prepared by reduction of [ 11 C]CO 2 with LiAlH 4 followed by reaction with HI) was reacted with norIomazenil in N,N -dimethylformamide and Bu 4 N + OH − for 1 min at 80 °C and purified by HPLC (C 18 , 34% CH 3 CN/H 2 O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [ 11 C]Iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [ 11 C]flumazenil PET and [ 123 I]Iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [ 11 C]Iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.
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reproducibility of spect measurement of benzodiazepine receptors in human brain with iodine 123 Iomazenil
The Journal of Nuclear Medicine, 1995Co-Authors: Anissa Abidargham, Sami S Zoghbi, Ronald M Baldwin, Yolanda Zeaponce, Marc Laruelle, Dennis S Charney, Paul B Hoffer, Mitchell S Gandelman, Penny Randall, Robert B. InnisAbstract:UNLABELLED: Iodine-123-Iomazenil is a SPECT radiotracer used to image and quantify benzodiazepine receptors. The reproducibility of the measurement of benzodiazepine receptors in human brain with [123I]Iomazenil and SPECT was investigated with a test/retest paradigm. METHODS: Six subjects underwent two experiments during a 1-wk interval. Iodine-123-Iomazenil was injected as a single bolus (12 mCi). The time-activity curves of the tracer in the arterial plasma were measured and corrected for metabolites. Regional time-activity curves of five brain regions were measured with the CERASPECT camera for 145 min postinjection with serial 2-min acquisitions. Data were analyzed using three kinetic models that included a two-compartment model, an unconstrained three-compartment model and a three-compartment model with a constraint on the nondisplaceable compartment. RESULTS: The results from the various analyses and fitting strategies were compared. The variability (average absolute difference between test and retest, expressed as a percentage of the mean of both measurements) was 10% to 17%, depending on the outcome measure and the fitting procedure. The most reproducible outcome measure was the regional tracer distribution volume relative to the total arterial concentration (VT'). VT' showed an average regional variability of 10% +/- 2%, with an intraclass correlation coefficient of 0.81. CONCLUSION: SPECT measurement of regional [123I]Iomazenil VT' is reproducible and reliable. The use of regional ratios results in a significant loss of information.
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evaluation of ultrafiltration for the free fraction determination of single photon emission computed tomography spect radiotracers β cit ibf and Iomazenil
Journal of Pharmaceutical Sciences, 1994Co-Authors: Mitchell S Gandelman, Sami S Zoghbi, Ronald M Baldwin, Yolanda Zeaponce, Robert B. InnisAbstract:An ultrafiltration system was evaluated for the free‐fraction measurement of SPECT radiotracers (β‐CIT, IBF, and Iomazenil) used in functional brain imaging. The effect of temperature, storage, centrifugal force, tracer concentration, and percentage filtered demonstrated a relative error of < 9%. As a result of the minimal temperature effect, 25 °C was employed for all measurements. A comparison of the ultrafiltration system with equilibrium dialysis revealed < 5% difference for β‐CIT and Iomazenil, but 16% for IBF. Additionally, the time and ease of operation considerably favored the ultrafiltration system. The precision quantitated by repetition was < 6% for between‐run and within‐run variability. In conclusion, ultrafiltration provided rapid results, demonstrated minor analytical errors, revealed generally good correlation with equilibrium dialysis, and allowed excellent precision.
