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ABSTRACT: The need for innovation in research is leading to an increased use of imaging biomarkers, which have shown to reduce timings and increase productivity, thus saving costs. PET and SPECT neurotransmission imaging has shown usefulness in the discovery and development of drugs for the central nervous system, providing unique information on drug-target interactions in the living human brain. Among the different therapeutic areas, antipsychotic drugs pioneered the application of these technologies in early phases of development. PET and SPECT radioligands for the most commonly targeted neurotransmission systems in the development of these drugs, such as the dopaminergic and serotoninergic systems are available, thus fostering the inclusion of PET and SPECT studies in the antipsychotic drug development plans. Radioligands for other neurotransmission systems more recently implicated in the pathophysiology of schizophrenia, such as the glutamatergic system, are being currently investigated. This review focuses on neurotransmission PET and SPECT aiming to serve as a guidance for procedure requirements and methodology choices to be applied in antipsychotic drug development, through specific examples. Cutting-edge study designs and quantification approaches will be reviewed. Finally, some clues to get the most out of the PET and SPECT studies in the development of antipsychotic drugs will be provided.
Current Medicinal Chemistry 11/2012; · 4.86 Impact Factor
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Iluminada Corripio,
Alcides Ferreira,
Maria J Portella,
Víctor Pérez,
María J Escartí,
Maria Del Valle Camacho,
Rosa B Sauras,
Anna Alonso,
Eva Ma Grasa,
Ignasi Carrió, Ana M Catafau,
Enric Alvarez
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ABSTRACT: Levels above 75% of striatal dopamine 2 receptor occupancy (D2RO) have been associated with extrapyramidal symptoms (EPS). The aim of the present study is to investigate the relationship between D2RO and EPS in a sample of psychotic patients in current treatment with both typical and atypical antipsychotics. Brain iodine-123-iodobenzamide single photon emission computed tomography ((123)I-IBZM SPECT) was performed in 81 patients taking stable doses of haloperidol, risperidone, olanzapine, quetiapine, clozapine or ziprasidone. First, the degree of D2RO and Positive and Negative Syndrome Scale (PANSS) scores was compared between the group of patients who presented EPS and the group free of EPS. Afterwards, these variables were compared among the different antipsychotic medications. The group with EPS presented means of D2RO significantly higher than the group free of EPS. Significant differences in D2RO were found in clozapine, quetiapine and ziprasidone groups compared with the haloperidol group. No differences were observed between either olanzapine or risperidone and haloperidol. No quetiapine- or clozapine-treated patients developed EPS. Haloperidol and risperidone demonstrated a relationship between striatal D2RO and EPS. The findings suggest that higher D2RO is related to appearance of EPS. Occupancy in the group with EPS was in agreement with previous studies that suggested a high degree of D2RO is necessary for the occurrence of EPS.
Psychiatry Research 01/2012; 201(1):73-7. · 2.52 Impact Factor
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Santiago Bullich,
Mark Slifstein,
Jan Passchier,
N Venkatesha Murthy,
Lawrence S Kegeles,
Jong-Hoon Kim,
Xiaoyan Xu,
Roger N Gunn,
Raul Herance,
Juan Domingo Gispert,
Antonio Gutiérrez,
Magí Farré,
Marc Laruelle, Ana M Catafau
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ABSTRACT: (11)C-GSK931145 is a novel radioligand suitable for imaging the glycine transporter 1 (GlyT-1) in brain. In the present study, human dosimetry is estimated from baboon and human biodistribution data.
Three baboons and eight healthy human volunteers underwent whole-body positron emission tomography (PET) scans. Human dosimetry was estimated using three different region-of-interest (ROI) delineation methods that ranged in their complexity and execution time: ROIs drawn on anterior-posterior compressed PET images, on subsamples of the organs, and covering the whole-organ. Residence times for each organ were calculated as the area under the time-activity curves divided by the injected activity. Radiation dose estimates were calculated from organ residence times using the OLINDA/EXM software package.
The overall distribution of activity was similar in baboons and humans. Early scans presented high activity in the liver, and moderate activity in the lungs and kidneys. The principal route of clearance was intestinal and no urinary excretion was observed. The limiting organ with the highest radiation-absorbed dose was the liver. The mean effective dose in humans was 4.02 μSv/MBq (male phantom) and 4.95 μSv/MBq (female phantom) (ROIs drawn on subsamples of the organs). The human effective dose estimated from baboon data was ~15% larger than the effective dose estimated from human data.
Human PET imaging of the glycine transporter-1 with (11)C-GSK931145 results in a moderate effective human radiation dose, which allows for multiple PET examinations in the same individual. Among the three methods compared to delineate ROIs, the organ subsampling method shows the best balance between quantitative accuracy and practical application.
Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 08/2011; 13(4):776-84. · 2.47 Impact Factor
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Roger N Gunn,
Venkatesha Murthy, Ana M Catafau,
Graham Searle,
Santiago Bullich,
Mark Slifstein,
Daniele Ouellet,
Stefano Zamuner,
Raul Herance,
Cristian Salinas,
Ricardo Pardo-Lozano,
Eugenii A Rabiner,
Magi Farre,
Marc Laruelle
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ABSTRACT: The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT-1 PET molecular imaging tool to aid drug development and dose selection. We report on [(11) C]GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 inhibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of [(11) C]GSK931145 and the plasma-occupancy relationship of GSK1018921. [(11) C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (f(P) : 0.8 vs. 8%) and delivery (K(1) : 0.025 vs. 0.126 ml cm(-3) min(-1) ) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(V(T) ): 29-38%), but was improved using a pseudo reference tissue model (VAR(BP(ND) ): 16-23%). GSK1018921 EC(50) estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively.
Synapse 06/2011; 65(12):1319-32. · 2.94 Impact Factor
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ABSTRACT: Brain positron emission tomography (PET) is a useful technique for estimating the neuroreceptor occupancy of a drug in vivo. In the absence of a reference region, occupancy can be obtained from an "occupancy plot" with ordinary least squares (OLS) regression. However, OLS has been found to return inefficient occupancy estimations. The aim of this study was to improve the accuracy and precision of occupancy estimations.
Within a simulation framework, the efficiency of several model II regression approaches (accounting for error in the independent variable) and restricted maximum likelihood estimator (REML, specifically modeling the drug occupancy) was compared to the efficiency of OLS.
Efficiency of REML was 171%-210% the efficiency of OLS, while model II regressions were found to be substantially less efficient.
In the absence of a reference region, it is recommended to use occupancy REML instead of OLS in order to increase the validity of occupancy estimations and thus decrease the costs of PET research.
Medical Physics 05/2011; 38(5):2558-62. · 2.83 Impact Factor
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Iluminada Corripio,
María J Escartí,
Maria J Portella,
Víctor Pérez,
Eva Grasa,
Rosa B Sauras,
Anna Alonso,
Gemma Safont,
M Valle Camacho,
Rosa Dueñas,
Belén Arranz,
Luis San, Ana M Catafau,
Ignasi Carrió,
Enric Alvarez
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ABSTRACT: There is as yet no definite prognostic marker to determine whether a first-episode psychosis will become schizophrenia or not. The aim of the present study is to address whether the mechanism of sensitization of the subcortical dopaminergic pathway - yielding to an increase of the postsynaptic D2 receptors - may serve as a prognostic marker of clinical outcome in drug naïve patients with a first-episode psychosis, by means of a prospective and multicentric study with untreated first-episode psychosis patients (n=37). 123I-IBZM SPECT was performed at the time of the inclusion in the study, before antipsychotic medication was initiated. One year later, patients were assessed again so as to determine their diagnosis. There was a significant group effect at baseline in D2 Striatal/Frontal (S/F) ratios (F=10.2, p<0.001). Bonferroni posthoc comparisons attested significant differences between diagnosis (p=0.006), and between schizophrenia and control groups (p<0.001) but no differences between non-schizophrenia and control groups (p=0.9). The logistic regression model showed that D2R binding (p=0.02) and PAS (Premorbid Adjustment Scale) adulthood score (p=0.03) were predictive of the final diagnosis (schizophrenia/non-schizophrenia; Nagelkerke R(2)=0.59; X(2)=11.08, p=0.001). These findings replicate previous results on the usefulness of D2R binding as an objective prognostic parameter, together with the evaluation of premorbid adjustment, of the evolution of first-episode psychosis. In this regard, the results may provide a new view in the approach of early and personalized treatment in the debut of a psychosis.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 04/2011; 21(12):861-6. · 3.68 Impact Factor
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ABSTRACT: The aim of this study was to assess human striatal dopamine receptor 2 (D(2)) and cortical 5-hydroxytryptamine receptor 2A (5-HT(2A)) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics-receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials.
D(2) and 5-HT(2A) occupancy were measured over time (both at the time of maximum [T(max); 6 ± 2 h] and at the time of minimum [T(trough); 24 ± 4 h] plasma concentration after dosing) by means of (123)I-iodobenzamide and (123)I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers-D(2) occupancy measured at 48 (n = 9) and 56 mg (n = 9) and 5-HT(2A) occupancy at 56 mg (n = 9); study B consisted of D(2) and 5-HT(2A) occupancy measured in 12 stabilized-schizophrenia patients on stable doses (16-18 d of 56 mg/d) after washout of previous medication; and study C included D(2) occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n = 10) on stable doses (18-21 d) of SB-773812 (100 mg/d; n = 7) or risperidone (6 mg/d; n = 3).
Study A showed less than 30% D(2) occupancy at T(max), maintained at T(trough). 5-HT(2A) occupancy was 74%-97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D(2) occupancy. 5-HT(2A) occupancy ranged from 91% to 100%. In study C, SB-773812-induced D(2) occupancy was 60.3% ± 13.3% at T(max) and 55.1% ± 4.9% at T(trough). The pharmacokinetics-receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC(50)) of 92.7 ± 13.5 ng/mL for D(2) and 2.11 ± 0.50 ng/mL for 5-HT(2A).
In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D(2) occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics-receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.
Journal of Nuclear Medicine 03/2011; 52(4):526-34. · 6.38 Impact Factor
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ABSTRACT: [(11)C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D(1) receptor (R) over the 5-HT(2A) R in vitro, has shown lower selectivity in vivo, hampering measurement of D(1) R in the cortex. [(11)C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [(11)C]NNC112 in vivo D(1) R selectivity, and (2) develop a feasible methodology for imaging cortical D(1) R without contamination by 5-HT(2A) R. Seven healthy volunteers underwent [(11)C]NNC112 PET scans at baseline and after a 5-HT(2A) R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BP(ND) change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BP(ND) in the cortical (approximately 30%) and limbic regions (approximately 20%) but not in the striatum, which contains a much lower amount of 5-HT(2A) R. Therefore, ketanserin allows D(1) R signal to be detected by [(11)C]NNC112 PET without significant 5-HT(2A) R contamination. These data confirm the presence of a significant 5-HT(2A) R contribution to cortical [(11)C]NNC112 signal, and call for caution in the interpretation of published [(11)C]NNC112 PET findings on cortical D(1) R in humans. In the absence of more selective ligands, [(11)C]NNC112 PET with ketanserin can be used for cortical D(1) R imaging in vivo.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2009; 30(5):985-93. · 5.46 Impact Factor
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ABSTRACT: [11C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D1 receptor (R) over the 5-HT2A R in vitro, has shown lower selectivity in vivo, hampering measurement of D1 R in the cortex. [11C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [11C]NNC112 in vivo D1 R selectivity, and (2) develop a feasible methodology for imaging cortical D1 R without contamination by 5-HT2A R. Seven healthy volunteers underwent [11C]NNC112 PET scans at baseline and after a 5-HT2A R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BPND change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BPND in the cortical (~30%) and limbic regions (~20%) but not in the striatum, which contains a much lower amount of 5-HT2A R. Therefore, ketanserin allows D1 R signal to be detected by [11C]NNC112 PET without significant 5-HT2A R contamination. These data confirm the presence of a significant 5-HT2A R contribution to cortical [11C]NNC112 signal, and call for caution in the interpretation of published [11C]NNC112 PET findings on cortical D1 R in humans. In the absence of more selective ligands, [11C]NNC112 PET with ketanserin can be used for cortical D1 R imaging in vivo.Keywords: [11C]NNC112; D1 receptors; ketanserin; PET; selectivity
Journal of Cerebral Blood Flow & Metabolism 12/2009; 30(5):985-993. · 5.01 Impact Factor
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ABSTRACT: Antipsychotic-induced D2 receptor occupancy values tend to be lower when measured with [(123)I]IBZM SPECT than with [(11)C]Raclopride PET. To clarify this issue, D2 receptor occupancy was measured in the same subjects using both techniques. Twenty patients with schizophrenia on monotherapy with risperidone (n=7; 3-9 mg/d), olanzapine (n=5; 5-20 mg/d) or clozapine (n=8; 150-450 mg/d) at stable doses, and ten healthy volunteers (HV) underwent both a [(123)I]IBZM SPECT and a [(11)C]Raclopride PET examinations in random order on different days within a week. Patients with schizophrenia were scanned at a fixed interval after last dose administration. Quantification of receptor availability was performed using the most conventional methods from the literature: the tissue ratio derived specific uptake ratios (SUR) were used for SPECT, and simplified reference tissue model (SRTM) derived binding potentials (BP(ND)) for PET. Analysis was performed using both occipital cortex and cerebellum as reference regions for both modalities. Striatal D2 receptor occupancy was measured as the percentage reduction of [(123)I]IBZM SUR or [(11)C]Raclopride BP(ND) compared to the population average measured in HV using the same modality. Occupancy values measured by SPECT were lower than those measured with PET, by 12.4% and 13.8% when occipital cortex and cerebellum were used as reference regions. This difference should be taken in consideration when interpreting reported antipsychotic striatal D2 receptor occupancy values from the literature.
NeuroImage 03/2009; 46(2):447-58. · 5.89 Impact Factor
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ABSTRACT: The (123)I-IBZM SPECT measured D(2) receptor occupancy (D(2)RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D(2) receptor occupancy (D( 2)RO) and plasma concentration (C(P)) in stabilized schizophrenic patients on clinically relevant doses using (123)I-IBZM SPECT; 2) To investigate the time course of AP-induced D(2)RO and corresponding C(P). Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D( 2)RO and C(P) were measured over time following a sparse-sampling experimental design, and individual PK and D(2)RO-time profiles were estimated using a population approach. Observed striatal D(2)RO and C(P) ranges were 28-75% and 9.4-60.5 ng/mL for risperidone, 22-84% and 8.6-89.5 ng/mL for olanzapine, 5-53% and 41.6-818.2 ng/mL for clozapine and 0-64% and 37.9-719.6 ng/mL for quetiapine. A PK-D(2)RO relationship was found for the four APs. D(2)RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D(2)RO and C(P) at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D(2)RO below 65%. D(2)RO patterns over time differ between AP. These results should be considered for accurate interpretation of D(2)RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.
Journal of Psychopharmacology 03/2008; 22(8):882-94. · 3.04 Impact Factor
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ABSTRACT: 123I-IBZM single photon emission computed tomography (SPECT) is a widely used method to measure D(2) receptor availability. However, test-retest variability and reliability have not been reported yet. This study aimed to further characterize 123I-IBZM SPECT in healthy volunteers (HVs), by assessing (1) pseudoequilibrium interval after bolus injection; (2) normal specific uptake ratio (SUR) values using filtered-backprojection (FBP); and the iterative reconstruction algorithm ordered-subsets expectation maximization (OSEM); (3) test-retest variability and reliability (intraclass correlation coefficient); and (4) influence of OSEM on test-retest variability and reliability.
Ten HVs (Group A) were scanned twice 48 h apart for test-retest variability and reliability measurements, and n = 4 of them were sequentially scanned over time. Eighteen HVs (Group B) were scanned once at pseudoequilibrium. For reconstruction FBP was used. Test-retest scans were reconstructed in addition using OSEM. SPECT-MRI coregistration was used for region of interest drawing.
Pseudoequilibrium was achieved at 90 min postinjection (p.i.) and maintained until the end of the SPECT session (n = 4), and mean SUR at this time point was 0.96 +/- 0.14 (Groups A + B, n = 28). Mean SUR at test was 0.96 +/- 0.19 and at retest 0.94 +/- 0.19 (Group A, n = 10). Using FBP, test-retest variability was (12.7 +/- 9.6)% and reliability was 0.74. Using OSEM with 18 equivalent iterations, test-retest variability and reliability were improved to (6.5 +/- 5.2)% and 0.84, respectively.
123I-IBZM SPECT imaging using the bolus injection and a single scan at 90 min p.i. is a reproducible method showing acceptable test-retest variability and reliability. Test-retest variability and reliability can be substantially improved using OSEM with 12-36 equivalent iterations.
Synapse 02/2008; 62(1):62-9. · 2.94 Impact Factor
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Ana M Catafau,
Victor Perez,
Pedro Plaza,
Juan-Carlos Pascual,
Santiago Bullich,
Marina Suarez,
Maria M Penengo,
Iluminada Corripio,
Dolors Puigdemont,
Monica Danus,
Javier Perich,
Enric Alvarez
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ABSTRACT: To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo (123)I-ADAM SPECT.
(123)I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc.
Measures of SERT availability by means of (123)I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day. (123)I-ADAM SPECT measures of SERT availability from a group of ten previously studied age-matched healthy volunteers were used for comparison. The relationship between percentages of SERTocc and paroxetine Cp was studied using an E (max) model.
Mean SERTocc values were 66.4 +/- 9.5% in midbrain, 63.0 +/- 9.6% in thalamus, and 61.3 +/- 10.9% in striatum. No significant differences in SERTocc were found among these three regions. No significant differences in mean SERT availability were found in any region between drug-free MDD patients (midbrain = 1.14 +/- 0.15; thalamus = 0.85 +/- 0.13; striatum = 0.70 +/- 0.07) and healthy volunteers (midbrain = 1.19 +/- 0.22; thalamus = 0.96 +/- 0.14; striatum = 0.67 +/- 0.15). The E (max) model returned a SERTocc(max) = 70.5% and a Cp(50) = 2.7 ng/ml.
Using (123)I-ADAM SPECT, treatment with paroxetine 20 mg/day leads to more than 60% SERTocc on average in cerebral regions with known high SERT density. Data from this study do not support the existence of SERT availability differences between drug-free MDD patients and healthy volunteers. Finally, the E (max) model is suitable for the study of paroxetine Cp relationship to (123)I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic-pharmacodynamic relationships in drug development.
Psychopharmacologia 01/2007; 189(2):145-53. · 4.08 Impact Factor
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ABSTRACT: The objective of the study is to investigate whether dopamine D2 receptor occupancy by risperidone and plasma levels over time can account for therapeutic efficacy and the latency period to response. Thirty-eight examinations with (123)I-IBZM single photon emission computed tomography were performed on 22 patients with schizophrenia, at diagnosis, 48 h after starting risperidone treatment and at a stable dose. Risperidone plasma levels were determined and psychopathologic evaluations (Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale) were carried out. No differences in the striatal/occipital (S/O) ratio or plasma levels were found between examinations at the 48-h time point and when a stable dose level had been established, so these parameters could not account for the latency period required for clinical response. D2 receptor occupancy at 48 h correlated positively with clinical improvement after 2 weeks of treatment. Therefore, if these results are confirmed, D2 receptor occupancy at the beginning of treatment with risperidone may be a predictor of subsequent clinical response.
Psychiatry Research 01/2007; 148(2-3):175-83. · 2.52 Impact Factor
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Ana M Catafau,
Monica Danus,
Santiago Bullich,
Jordi Llop,
Javier Perich,
Vincent J Cunningham,
Pedro Plaza,
Maria M Penengo,
Jos L H Eersels,
Lisa Squassante,
Domenec Ros,
Manel Barbanoj
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ABSTRACT: With the aim of characterizing radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) as a SPECT ligand for subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), tracer kinetic compartmental analyses were compared with the tissue ratio method (TR). The pseudoequilibrium interval after a single bolus injection was identified, and a reference database of specific uptake ratio (SUR) values was obtained. Within-scan and between-subject variability was also assessed.
Nineteen healthy men (mean age +/- SD, 24.4 +/- 3.3 y) were included and separated into 2 groups. Dynamic scans with venous blood sampling from 0 to 470 min after a single bolus injection of (123)I-R91150 was completed for 7 of the 9 subjects included in group A, and in one of them compartmental modeling was performed with an arterial blood input function using 1-tissue-compartment (1TC) and 2-tissue-compartment (2TC) models. Binding potential (BP) using the simplified reference tissue model (SRTM) (BP(SRTM)) and SUR values using TR over time were also calculated. The 10 remaining subjects (group B) underwent a single scan at pseudoequilibrium with the aim of improving the precision of mean normal SUR estimates. Regions of interest in cortical regions and basal ganglia for specific uptake, and in cerebellum for nonspecific uptake, were manually drawn on each subject's MR images and translated to the corresponding SPECT slices after coregistration.
The 1TC model correlated well with the 2TC model (BP(2TC) = 1.04.BP(1TC) - 0.01, R(2) = 0.98), and both methods correlated with BP(SRTM) and SUR with little bias (BP(1TC) = 1.10 BP(SRTM) + 0.03, R(2) = 0.98; BP(2TC) = 1.15 BP(SRTM) + 0.01, R(2) = 0.98; BP(SRTM) = 0.99 SUR(mean) + 0.01, R(2) = 0.98). SUR values stabilized from 180 min after injection in most cortical regions, ranging from 0.51 +/- 0.10 in the orbitofrontal region to 0.27 +/- 0.09 in the parietal region. Within-scan and between-subject variability among regions ranged from 10% to 14.8%, and from 18.3% to 35.4%, respectively.
(123)I-R91150 distribution agrees with autoradiography results, showing highly specific binding in cortical regions. The correlations found among 1TC, 2TC, SRTM, and TR outcome measurements support the use of TR for quantification of 5-HT(2A) receptor binding with (123)I-R91150 SPECT and a simple protocol avoiding arterial blood sampling and serial scanning over time.
Journal of Nuclear Medicine 07/2006; 47(6):919-28. · 6.38 Impact Factor
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ABSTRACT: As part of the radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) characterization study, ketanserin challenges were performed on healthy volunteers with the aim of assessing the specificity of (123)I-R91150 binding to subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), the sensitivity of (123)I-R91150 SPECT in measuring ligand displacement, the relationship between ketanserin plasma concentrations and (123)I-R91150 displacement, and the suitability of the cerebellum as a reference region for quantification.
Dynamic SPECT was performed on 6 healthy men (mean age +/- SD, 21 +/- 0.89 y) from the time of (123)I-R91150 injection until 470 min afterward. Ketanserin was administered intravenously at 210 min after injection at 3 doses: 0.1 mg/kg (n = 2), 0.05 mg/kg (n = 2), and 0.015 mg/kg (n = 2). Blood samples for measurement of ketanserin plasma concentrations were drawn. MRI was performed on all subjects and coregistered to the SPECT data for region-of-interest drawing on cortical regions and cerebellum. The simplified reference tissue model (SRTM) was considered the gold standard for quantification, and results were compared with those obtained with the tissue ratio method (TR). The percentage (123)I-R91150 displacement was calculated with both methods as the percentage difference between baseline and postketanserin scans.
Depending on the cerebral regions with the maximum ketanserin dose studied, SRTM and TR mean displacements were 57.1%-95.4% and 71.9%-101.2%, respectively, for the 0.1 mg/kg dose; 51.7%-91.4% and 56.7%-102.8%, respectively, for the 0.05 mg/kg dose; and 7.7%-54.5% and 13.8%-47.0%, respectively, for the lowest dose, 0.015 mg/kg. A good correlation was found between the 2 methods. No ketanserin-induced displacement was observed in the cerebellum time-activity curves, supporting the use of the cerebellum as a reference region. The relationship between displacement and ketanserin plasma concentration fit with a rectangular hyperbola, with a 5.6 ng/mL concentration associated with 50% of the maximum displacement (EC(50)). EC(50) values calculated using occupancies derived both with SRTM and with TR were in good agreement.
(123)I-R91150 SPECT is sensitive enough to measure ketanserin dose-dependent displacement in cerebral regions rich in 5-HT(2A) receptors. These results support the selectivity of (123)I-R91150 for 5-HT(2A) receptors and its use as a SPECT ligand for measurements of drug-induced 5-HT(2A) receptor occupancy in humans.
Journal of Nuclear Medicine 07/2006; 47(6):929-37. · 6.38 Impact Factor
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ABSTRACT: In a preliminary 123I-IBZM SPECT study in first-episode psychosis, a relationship between striatal dopaminergic D2 receptor (D2R) binding and premorbid adjustment was suggested. These results were replicated in the present study (n = 18), and D2R binding at diagnosis predicted a high probability for schizophrenia outcome by 2-year follow-up. The present findings contribute to the evidence of abnormal D2R binding in schizophrenia and suggest that SPECT might be useful for outcome prediction in first-episode psychosis.
NeuroImage 02/2006; 29(2):662-6. · 5.89 Impact Factor
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Ana M Catafau,
Víctor Pérez,
María M Penengo,
Santiago Bullich,
Mónica Danús,
Dolors Puigdemont,
Juan C Pascual,
Iluminada Corripio,
Jordi Llop,
Javier Perich,
Enric Alvarez
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ABSTRACT: (123)I-ADAM (2-([2-([dimethylamino]methyl)phenyl]thio)-5-(123)I-iodophenylamine) has been recently proposed as a new serotonin transporter (SERT) ligand for SPECT. The objective of this study was to characterize (123)I-ADAM in healthy volunteers. (123)I-ADAM distribution in the normal brain, pseudoequilibrium interval after a single injection, normal specific uptake values, and long-term test-retest variability and reliability were investigated.
Ten healthy volunteers underwent 2 SPECT sessions under the same conditions 47.6 +/- 24.0 d apart. Scans were sequentially acquired from the time of (123)I-ADAM intravenous injection up to 12 h after injection. Regions of interest (ROIs) for cerebellum (C), midbrain, thalamus, striatum, mesial temporal region, and cortex were drawn on MR images and pasted to corresponding SPECT slices after coregistration. Specific uptake ratios (SURs) at pseudoequilibrium and the simplified reference tissue model (SRTM) methods were used for quantification. SURs were obtained as ([region - C]/C) at each time point. Test-retest variability and reliability (intraclass correlation coefficient [ICC]) were calculated.
The highest (123)I-ADAM specific uptake was found in the midbrain and thalamus, followed by the striatum and mesial temporal region. Quantification results using SUR and SRTM were correlated with R = 0.93 (test) and R = 0.94 (retest). SURs remained stable in all regions from 4 to 6 h after injection. Using SUR, test-retest variability/ICC were 13% +/- 11%/0.74 in midbrain, 16% +/- 13%/0.63 in thalamus, 19% +/- 18%/0.62 in striatum, and 22% +/- 19%/0.05 in mesial temporal region.
(123)I-ADAM accumulates in cerebral regions with high known SERT density. The optimal imaging time for (123)I-ADAM SPECT quantification is suggested to be from 4 to 6 h after a single injection. Long-term test-retest variability and reliability found in the midbrain are comparable to that reported with other (123)I-labeled SPECT ligands. These results support the use of (123)I-ADAM SPECT for SERT imaging after a single injection in humans.
Journal of Nuclear Medicine 09/2005; 46(8):1301-9. · 6.38 Impact Factor
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ABSTRACT: The aim of this study was to compare striatal dopaminergic D2 receptor occupancy (D2 RO) induced by ziprasidone and haloperidol and its relationship with clinical response and extrapyramidal side effects (EPS) in patients with acute psychosis exacerbation.
Twenty patients hospitalized with an acute psychosis exacerbation were randomised in a single-blind study to receive either ziprasidone (80-120 mg/day) or haloperidol (5-20 mg/day) for more than 2 weeks. When stable doses were achieved, data on 123I-IBZM single-photon emission computed tomography (SPECT), as well as data on clinical efficacy (positive and negative symptoms scale [PANSS]) and EPS (Simpson Angus scale [SAS]), were compared between the two groups of patients. Clinical response was defined as a percentage of change of >30% in PANSS. Striatal D2 RO and clinical data were also compared between responders and nonresponders on each treatment group.
All patients on haloperidol and four patients on ziprasidone showed EPS. Mean D2 RO was significantly higher in the haloperidol (74.7+/-3.5) than in the ziprasidone (60.2+/-14.4) group (Mann Whitney U-test [M-W U-test] 8.50; p=0.002). Five patients were responders, and five were nonresponders on each group of treatment. Haloperidol responders and nonresponders did not differ in D2 RO, duration of treatment, doses or EPS. Ziprasidone responders were on higher doses than nonresponders and showed higher D2 RO although below 74%. A positive correlation of ziprasidone D2 RO was found with dose (r Spearman 0.87; p=0.001) and with SAS scores (r Spearman 0.88; p=0.001).
Ziprasidone induces lower D2 RO and EPS than haloperidol, which is consistent with an atypical antipsychotic profile. A direct relationship of ziprasidone D2 RO with dose, clinical efficacy and EPS has been found in this study. These data suggest that high ziprasidone doses might be more beneficial in patients with psychosis exacerbation and claim for caution regarding EPS appearance with such high dosages.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/2005; 29(1):91-6. · 3.25 Impact Factor
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ABSTRACT: Imaging with (123)I-Ioflupane single-photon emission computed tomography (SPECT) is a marker of nigrostriatal neuronal integrity, allowing differentiation of parkinsonism with loss of dopaminergic terminals (presynaptic Parkinson syndrome [PS]) from parkinsonism without nigrostriatal degeneration. This study assessed SPECT imaging in 118 patients with clinically uncertain parkinsonian syndromes (CUPS). In 36% of patients with presynaptic PS and 54% with nonpresynaptic PS, imaging results were not consistent with the initial diagnosis. After imaging, diagnosis was changed in 52% of patients. All patients with a final diagnosis of presynaptic PS had an abnormal image, whereas 94% of patients with nonpresynaptic PS had a normal scan. Imaging increased confidence in diagnosis, leading to changes in clinical management in 72% of patients. Consequently, visual assessment of (123)I-Ioflupane SPECT may have a significant impact on the clinical management of CUPS patients.
Movement Disorders 11/2004; 19(10):1175-82. · 4.51 Impact Factor
