74 results on '"Moerlein SM"'
Search Results
2. Non-steady-state measurement of in vivo radioligand binding with positron emission tomography: specificity analysis and comparison with in vitro binding
- Author
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Perlmutter, JS, primary, Moerlein, SM, additional, Hwang, DR, additional, and Todd, RD, additional
- Published
- 1991
- Full Text
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3. PET Quantification of [ 18 F]VAT in Human Brain and Its Test-Retest Reproducibility and Age Dependence.
- Author
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O'Donnell JL, Soda AK, Jiang H, Norris SA, Maiti B, Karimi M, Campbell MC, Moerlein SM, Tu Z, and Perlmutter JS
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- Humans, Adult, Middle Aged, Aged, Male, Female, Reproducibility of Results, Young Adult, Aged, 80 and over, Aging metabolism, Radiopharmaceuticals pharmacokinetics, Vesicular Acetylcholine Transport Proteins metabolism, Brain diagnostic imaging, Brain metabolism, Positron-Emission Tomography methods, Piperidines pharmacokinetics, Piperidines metabolism
- Abstract
Molecular imaging of brain vesicular acetylcholine transporter provides a biomarker to explore cholinergic systems in humans. We aimed to characterize the distribution of, and optimize methods to quantify, the vesicular acetylcholine transporter-specific tracer (-)-(1-(8-(2-[
18 F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([18 F]VAT) in the brain using PET. Methods: Fifty-two healthy participants aged 21-97 y had brain PET with [18 F]VAT. [3 H]VAT autoradiography identified brain areas devoid of specific binding in cortical white matter. PET image-based white matter reference region size, model start time, and duration were optimized for calculations of Logan nondisplaceable binding potential (BPND ). Ten participants had 2 scans to determine test-retest variability. Finally, we analyzed age-dependent differences in participants. Results: [18 F]VAT was widely distributed in the brain, with high striatal, thalamic, amygdala, hippocampal, cerebellar vermis, and regionally specific uptake in the cerebral cortex. [3 H]VAT autoradiography-specific binding and PET [18 F]VAT uptake were low in white matter. [18 F]VAT SUVs in the white matter reference region correlated with age, requiring stringent erosion parameters. Logan BPND estimates stabilized using at least 40 min of data starting 25 min after injection. Test-retest variability had excellent reproducibility and reliability in repeat BPND calculations for 10 participants (putamen, 6.8%; r > 0.93). We observed age-dependent decreases in the caudate and putamen (multiple comparisons corrected) and in numerous cortical regions. Finally, we provide power tables to indicate potential mean differences that can be detected between 2 groups of participants. Conclusion: These results validate a reference region for BPND calculations and demonstrate the viability, reproducibility, and utility of using the [18 F]VAT tracer in humans to quantify cholinergic pathways., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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4. Principal Component Analysis of Striatal and Extrastriatal D2 Dopamine Receptor Positron Emission Tomography in Manganese-Exposed Workers.
- Author
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Criswell SR, Searles Nielsen S, Dlamini WW, Warden MN, Perlmutter JS, Sheppard L, Moerlein SM, Lenox-Krug J, Checkoway H, and Racette BA
- Subjects
- Brain diagnostic imaging, Corpus Striatum diagnostic imaging, Humans, Principal Component Analysis, Manganese toxicity, Positron-Emission Tomography
- Abstract
The relationships between the neurotoxicant manganese (Mn), dopaminergic pathology, and parkinsonism remain unclear. Therefore, we used [11C](N-methyl)benperidol (NMB) positron emission tomography to investigate the associations between Mn exposure, striatal and extrastriatal D2 dopamine receptors (D2R), and motor function in 54 workers with a range of Mn exposure. Cumulative Mn exposure was estimated from work histories, and all workers were examined by a movement specialist and completed a Grooved Pegboard test (GPT). NMB D2R nondisplaceable binding potentials (BPND) were calculated for brain regions of interest. We identified 2 principal components (PCs) in a PC analysis which explained 66.8% of the regional NMB BPND variance (PC1 = 55.4%; PC2 = 11.4%). PC1 was positively correlated with NMB binding in all regions and inversely correlated with age. PC2 was driven by NMB binding in 7 brain regions (all p < .05), positively in the substantia nigra, thalamus, amygdala, and medial orbital frontal gyrus and negatively in the nucleus accumbens, anterior putamen, and caudate. PC2 was associated with both Mn exposure status and exposure duration (years). In addition, PC2 was associated with higher Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) scores and slower GPT performance. We conclude Mn exposure is associated with both striatal and extrastriatal D2R binding. Multifocal alterations in D2R expression are also associated with motor dysfunction as measured by both the GPT and UPDRS3, demonstrating a link between Mn exposure, striatal and extrastriatal D2R expression, and clinical neurotoxicity., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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5. [11C]dihydrotetrabenazine Positron Emission Tomography in Manganese-Exposed Workers.
- Author
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Criswell SR, Nielsen SS, Warden MN, Perlmutter JS, Moerlein SM, Sheppard L, Lenox-Krug J, Checkoway H, and Racette BA
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- Adult, Aged, Carbon Radioisotopes, Female, Humans, Male, Middle Aged, Occupational Diseases chemically induced, Tetrabenazine analogs & derivatives, Young Adult, Manganese adverse effects, Occupational Exposure adverse effects, Parkinsonian Disorders chemically induced, Positron-Emission Tomography
- Abstract
Objective: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2)., Methods: Basal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkinsonism were examined by mixed linear regression., Results: Thalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m-yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P = 0.003)., Conclusion: Mn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on monoaminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity.
- Published
- 2020
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6. Selective D2 receptor PET in manganese-exposed workers.
- Author
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Criswell SR, Warden MN, Searles Nielsen S, Perlmutter JS, Moerlein SM, Sheppard L, Lenox-Krug J, Checkoway H, and Racette BA
- Subjects
- Adult, Aged, Benperidol pharmacology, Brain, Case-Control Studies, Female, Humans, Male, Middle Aged, Multimodal Imaging, Neuroimaging, Parkinsonian Disorders complications, Parkinsonian Disorders diagnosis, Parkinsonian Disorders metabolism, Positron-Emission Tomography, Young Adult, Benperidol metabolism, Manganese toxicity, Manganese Poisoning diagnostic imaging, Receptors, Dopamine D2 metabolism
- Abstract
Objective: To investigate the associations between manganese (Mn) exposure, D2 dopamine receptors (D2Rs), and parkinsonism using [
11 C](N-methyl)benperidol (NMB) PET., Methods: We used NMB PET to evaluate 50 workers with a range of Mn exposure: 22 Mn-exposed welders, 15 Mn-exposed workers, and 13 nonexposed workers. Cumulative Mn exposure was estimated from work histories, and movement disorder specialists examined all workers. We calculated NMB D2R nondisplaceable binding potential (BPND) for the striatum, globus pallidus, thalamus, and substantia nigra (SN). Multivariate analysis of covariance with post hoc descriptive discriminate analysis identified regional differences by exposure group. We used linear regression to examine the association among Mn exposure, Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) score, and regional D2R BPND., Results: D2R BPND in the SN had the greatest discriminant power among exposure groups ( p < 0.01). Age-adjusted SN D2R BPND was 0.073 (95% confidence interval [CI] 0.022-0.124) greater in Mn-exposed welders and 0.068 (95% CI 0.013-0.124) greater in Mn-exposed workers compared to nonexposed workers. After adjustment for age, SN D2R BPND was 0.0021 (95% CI 0.0005-0.0042) higher for each year of Mn exposure. Each 0.10 increase in SN D2R BPND was associated with a 2.65 (95% CI 0.56-4.75) increase in UPDRS3 score., Conclusions and Relevance: Nigral D2R BPND increased with Mn exposure and clinical parkinsonism, indicating dose-dependent dopaminergic dysfunction of the SN in Mn neurotoxicity., (© 2018 American Academy of Neurology.)- Published
- 2018
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7. [ 18 F]FDOPA positron emission tomography in manganese-exposed workers.
- Author
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Criswell SR, Nielsen SS, Warden M, Perlmutter JS, Moerlein SM, Flores HP, Huang J, Sheppard L, Seixas N, Checkoway H, and Racette BA
- Subjects
- Adult, Corpus Striatum diagnostic imaging, Cross-Sectional Studies, Dihydroxyphenylalanine analogs & derivatives, Female, Humans, Magnetic Resonance Imaging, Male, Manganese Poisoning diagnostic imaging, Middle Aged, Occupational Diseases chemically induced, Occupational Diseases diagnostic imaging, Parkinsonian Disorders diagnostic imaging, Parkinsonian Disorders metabolism, Positron-Emission Tomography, Welding, Corpus Striatum metabolism, Manganese Poisoning metabolism, Occupational Diseases metabolism, Occupational Exposure, Parkinsonian Disorders chemically induced
- Abstract
Occupational manganese (Mn) exposure is associated with the development of parkinsonism; however, the mechanism of neurotoxicity is unknown. Brain positron emission tomography (PET) imaging provides a non-invasive method of assessing dopamineric neuronal function. 6-[
18 F]fluoro-L-DOPA (FDOPA) PET reflects in-vivo nigrostriatal function, but results in Mn exposure are conflicting. The objective of this study was to investigate the association between Mn exposure secondary to occupational welding, FDOPA striatal uptake, and clinical parkinsonism as measured by Unified Parkinson Disease Rating Scale motor subscore 3 (UPDRS3) scores. FDOPA PET scans were acquired on 72 subjects (27 Mn-exposed welders, 14 other Mn-exposed workers, and 31 non-exposed subjects). We estimated cumulative welding exposure from detailed work histories, and a movement disorders specialist examined all subjects. Striatal volumes of interest were identified on aligned magnetic resonance imaging (MRI) for each subject. Specific striatal FDOPA uptake was calculated with a graphical analysis method. We used linear regression while adjusting for age to assess the association between welding exposure and FDOPA uptake in the caudate, anterior putamen, and posterior putamen. Compared to the non-exposed subjects, mean caudate FDOPA uptake was 0.0014min-1 (95% confidence interval [CI] 0.0008, 0.0020) lower in Mn-exposed welders and 0.0012min-1 (95% CI 0.0005, 0.0019) lower in other Mn-exposed workers (both p≤0.001). There was no clear dose-response association between caudate FDOPA uptake and Mn exposure or UPDRS3 scores. Mn-exposed welders and workers demonstrated lower caudate FDOPA uptake, indicating pre-synaptic dopaminergic dysfunction in Mn-exposed subjects that was not associated with clinical parkinsonism., (Copyright © 2017 Elsevier B.V. All rights reserved.)- Published
- 2018
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8. Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia.
- Author
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Eisenstein SA, Bogdan R, Chen L, Moerlein SM, Black KJ, Perlmutter JS, Hershey T, and Barch DM
- Subjects
- Adolescent, Adult, Anhedonia physiology, Brain diagnostic imaging, Brain metabolism, Catechol O-Methyltransferase genetics, Dopamine Plasma Membrane Transport Proteins genetics, Female, Humans, Male, Middle Aged, Psychotic Disorders diagnostic imaging, Receptors, Dopamine D4 genetics, Schizophrenia diagnostic imaging, Schizophrenia metabolism, Siblings, Young Adult, Psychotic Disorders genetics, Psychotic Disorders psychology, Receptors, Dopamine D2 genetics, Receptors, Dopamine D2 metabolism, Schizophrenia genetics, Schizophrenic Psychology
- Abstract
Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants (N = 124) were genotyped for DA-related polymorphisms in genes for DRD4, DRD2/ANKK1, DAT1, and COMT, which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants (N = 23) using PET scans with the D2R-selective, non-displaceable radioligand (N-[
11 C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2017
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9. Absorbed radiation dosimetry of the D 3 -specific PET radioligand [ 18 F]FluorTriopride estimated using rodent and nonhuman primate.
- Author
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Laforest R, Karimi M, Moerlein SM, Xu J, Flores HP, Bognar C, Li A, Mach RH, Perlmutter JS, and Tu Z
- Abstract
[
18 F]FluorTriopride ([18 F]FTP) is a dopamine D3 -receptor preferring radioligand with potential for investigation of neuropsychiatric disorders including Parkinson disease, dystonia and schizophrenia. Here we estimate human radiation dosimetry for [18 F]FTP based on the ex-vivo biodistribution in rodents and in vivo distribution in nonhuman primates. Biodistribution data were generated using male and female Sprague-Dawley rats injected with ~370 KBq of [18 F]FTP and euthanized at 5, 30, 60, 120, and 240 min. Organs of interest were dissected, weighed and assayed for radioactivity content. PET imaging studies were performed in two male and one female macaque fascicularis administered 143-190 MBq of [18 F]FTP and scanned whole-body in sequential sections. Organ residence times were calculated based on organ time activity curves (TAC) created from regions of Interest. OLINDA/EXM 1.1 was used to estimate human radiation dosimetry based on scaled organ residence times. In the rodent, the highest absorbed radiation dose was the upper large intestines (0.32-0.49 mGy/MBq), with an effective dose of 0.07 mSv/MBq in males and 0.1 mSv/MBq in females. For the nonhuman primate, however, the gallbladder wall was the critical organ (1.81 mGy/MBq), and the effective dose was 0.02 mSv/MBq. The species discrepancy in dosimetry estimates for [18 F]FTP based on rat and primate data can be attributed to the slower transit of tracer through the hepatobiliary track of the primate compared to the rat, which lacks a gallbladder. Out findings demonstrate that the nonhuman primate model is more appropriate model for estimating human absorbed radiation dosimetry when hepatobiliary excretion plays a major role in radiotracer elimination.- Published
- 2016
10. Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.
- Author
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Eisenstein SA, Bogdan R, Love-Gregory L, Corral-Frías NS, Koller JM, Black KJ, Moerlein SM, Perlmutter JS, Barch DM, and Hershey T
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- Adolescent, Adult, Alleles, Benperidol analogs & derivatives, Benperidol pharmacokinetics, Case-Control Studies, Corpus Striatum diagnostic imaging, Female, Heterozygote, Humans, Male, Middle Aged, Positron-Emission Tomography, Protein Binding, Radiopharmaceuticals pharmacokinetics, Receptors, Dopamine D2 chemistry, Receptors, Dopamine D2 metabolism, Ankyrin Repeat genetics, Corpus Striatum metabolism, Obesity genetics, Polymorphism, Single Nucleotide, Receptors, Dopamine D2 genetics, Schizophrenia genetics
- Abstract
In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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11. Sweet Dopamine: Sucrose Preferences Relate Differentially to Striatal D2 Receptor Binding and Age in Obesity.
- Author
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Pepino MY, Eisenstein SA, Bischoff AN, Klein S, Moerlein SM, Perlmutter JS, Black KJ, and Hershey T
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- Adolescent, Adult, Female, Glucose Tolerance Test, Humans, Magnetic Resonance Imaging, Male, Positron-Emission Tomography, Protein Binding, Taste physiology, Young Adult, Dopamine metabolism, Obesity metabolism, Receptors, Dopamine D2 metabolism, Sucrose metabolism
- Abstract
Alterations in dopaminergic circuitry play a critical role in food reward and may contribute to susceptibility to obesity. Ingestion of sweets releases dopamine in striatum, and both sweet preferences and striatal D2 receptors (D2R) decline with age and may be altered in obesity. Understanding the relationships between these variables and the impact of obesity on these relationships may reveal insight into the neurobiological basis of sweet preferences. We evaluated sucrose preferences, perception of sweetness intensity, and striatal D2R binding potential (D2R BPND) using positron emission tomography with a D2R-selective radioligand insensitive to endogenous dopamine, (N-[(11)C] methyl)benperidol, in 20 subjects without obesity (BMI 22.5 ± 2.4 kg/m(2); age 28.3 ± 5.4 years) and 24 subjects with obesity (BMI 40.3 ± 5.0 kg/m(2); age 31.2 ± 6.3 years). The groups had similar sucrose preferences, sweetness intensity perception, striatal D2R BPND, and age-related D2R BPND declines. However, both striatal D2R BPND and age correlated with sucrose preferences in subjects without obesity, explaining 52% of their variance in sucrose preference. In contrast, these associations were absent in the obese group. In conclusion, the age-related decline in D2R was not linked to the age-related decline in sweetness preferences, suggesting that other, as-yet-unknown mechanisms play a role and that these mechanisms are disrupted in obesity., (© 2016 by the American Diabetes Association.)
- Published
- 2016
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12. Correction: Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity.
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Eisenstein SA, Gredysa DM, Antenor-Dorsey JA, Green L, Arbeláez AM, Koller JM, Black KJ, Perlmutter JS, Moerlein SM, and Hershey T
- Published
- 2016
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13. Automated production of [¹⁸F]VAT suitable for clinical PET study of vesicular acetylcholine transporter.
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Yue X, Bognar C, Zhang X, Gaehle GG, Moerlein SM, Perlmutter JS, and Tu Z
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- Fluorine Radioisotopes standards, Humans, Molecular Structure, Naphthols chemistry, Piperidines chemistry, Piperidines standards, Quality Control, Radiopharmaceuticals chemistry, Radiopharmaceuticals standards, Fluorine Radioisotopes chemistry, Naphthols chemical synthesis, Piperidines chemical synthesis, Positron-Emission Tomography methods, Radiopharmaceuticals chemical synthesis, Vesicular Acetylcholine Transport Proteins metabolism
- Abstract
Automated production of a promising radiopharmaceutical (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([(18)F]VAT) for the vesicular acetylcholine transporter(VAChT) was achieved using a two-step procedure in a current Good Manufacturing Practices fashion. The production of [(18)F]VAT was accomplished in approximately 140 min, with radiochemical yield of ~15.0% (decay corrected), specific activity>111 GBq/µmol, radiochemical purity>99% and mass of VAT ~3.4 μg/batch (n>10). The radiopharmaceutical product meets all quality control criteria for human use, and is suitable for clinical PET studies of VAChT., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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14. Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity.
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Eisenstein SA, Gredysa DM, Antenor-Dorsey JA, Green L, Arbeláez AM, Koller JM, Black KJ, Perlmutter JS, Moerlein SM, and Hershey T
- Subjects
- Absorptiometry, Photon, Adipose Tissue metabolism, Adult, Animals, Binding, Competitive, Body Mass Index, Carbon Radioisotopes, Corpus Striatum metabolism, Delay Discounting, Female, Humans, Insulin-Secreting Cells metabolism, Linear Models, Male, Obesity diagnosis, Obesity psychology, Positron-Emission Tomography, Radioligand Assay, Young Adult, Insulin metabolism, Obesity metabolism, Receptors, Dopamine D2 metabolism, Reward
- Abstract
Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic factors, including β-cell function, interact to affect reward discounting in humans.
- Published
- 2015
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15. Neuroimaging Analysis of the Dopamine Basis for Apathetic Behaviors in an MPTP-Lesioned Primate Model.
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Tian L, Xia Y, Flores HP, Campbell MC, Moerlein SM, and Perlmutter JS
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- Animals, Cerebral Cortex diagnostic imaging, Dopaminergic Neurons diagnostic imaging, Goals, Macaca fascicularis, Macaca nemestrina, Magnetic Resonance Imaging, Male, Motor Activity, Organ Specificity, Parkinsonian Disorders metabolism, Parkinsonian Disorders psychology, Positron-Emission Tomography, Radiopharmaceuticals, Single-Blind Method, Tyrosine 3-Monooxygenase analysis, Apathy physiology, Cerebral Cortex pathology, Dopamine physiology, Dopaminergic Neurons pathology, Neuroimaging, Parkinsonian Disorders pathology
- Abstract
Apathy commonly occurs in Parkinson disease (PD) patients; however, the role of dopamine in the pathophysiology of apathy remains elusive. We previously demonstrated that dopaminergic dysfunction within the ventral tegmental area (VTA)-nucleus accumbens (NAcc) pathway contributes to the manifestation of apathetic behaviors in monkeys treated with the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We now extend these studies to identify dopaminergic dysfunction in cortical regions that correlate with development of apathetic behaviors. Specifically, we measured the effects of MPTP on monkeys' willingness to attempt goal directed behaviors, which is distinct from their ability to perform tasks. A total of 16 monkeys had baseline magnetic resonance imaging (MRI) and positron emission tomography (PET), using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2β-[11C]carbomethoxy-3β-(4-fluorophenyl)tropane (CFT). The monkeys received unilateral infusion of different doses of MPTP (0 - 0.31mg/kg) to produce a wide range of severity of motor parkinsonism. Eight weeks after MPTP, PET scans were repeated and animals were euthanized. Apathetic behavior and motor impairments were assessed blindly both pre- and post-MPTP infusion. Apathy scores were compared to in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with PET measures of dopaminergic terminals (DTBZ or CFT) in dorsal lateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (VMPFC), and insular cortex (IC). Among all the cortical regions assessed, forward step-wise regression analyses indicated that only stereologic cell counts in VTA, and not counts in the substantia nigra (SN), predict dopamine transporter changes in IC. Our findings suggest that dopaminergic dysfunction within the VTA-IC pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates.
- Published
- 2015
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16. Emotional Eating Phenotype is Associated with Central Dopamine D2 Receptor Binding Independent of Body Mass Index.
- Author
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Eisenstein SA, Bischoff AN, Gredysa DM, Antenor-Dorsey JA, Koller JM, Al-Lozi A, Pepino MY, Klein S, Perlmutter JS, Moerlein SM, Black KJ, and Hershey T
- Subjects
- Adult, Benperidol administration & dosage, Benperidol pharmacokinetics, Body Mass Index, Female, Humans, Male, Radiography, Surveys and Questionnaires, Brain diagnostic imaging, Brain metabolism, Emotions, Feeding Behavior, Obesity diagnostic imaging, Obesity metabolism, Positron-Emission Tomography, Receptors, Dopamine D2 metabolism
- Abstract
PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D2 receptor (D2R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D2R-selective and nondisplaceable radioligand (N-[(11)C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D2R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p<0.001), greater sensitivity to punishment (p=0.06), and lower non-food reward behavior (p<0.01). Across normal-weight and obese participants, self-reported emotional eating and non-food reward behavior positively correlated with striatal (p<0.05) and midbrain (p<0.05) D2R binding, respectively. In conclusion, an emotional eating phenotype may reflect altered central D2R function better than other commonly used obesity-related measures such as BMI.
- Published
- 2015
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17. Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates.
- Author
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Dugan LL, Tian L, Quick KL, Hardt JI, Karimi M, Brown C, Loftin S, Flores H, Moerlein SM, Polich J, Tabbal SD, Mink JW, and Perlmutter JS
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Animals, Carboxylic Acids administration & dosage, Disease Models, Animal, Dopamine metabolism, Double-Blind Method, Macaca fascicularis, Male, Neostriatum injuries, Neostriatum metabolism, Neuroprotective Agents administration & dosage, Parkinsonian Disorders chemically induced, Parkinsonian Disorders metabolism, Parkinsonian Disorders physiopathology, Placebos, Positron-Emission Tomography methods, Random Allocation, Substantia Nigra drug effects, Substantia Nigra injuries, Substantia Nigra metabolism, Treatment Outcome, Behavior, Animal drug effects, Carboxylic Acids pharmacology, Neostriatum drug effects, Neuroprotective Agents pharmacology, Parkinsonian Disorders drug therapy
- Abstract
Objective: We evaluated the efficacy of the potent antioxidant C3 to salvage nigrostriatal neuronal function after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure in nonhuman primates. C3 is a first-in-class functionalized water-soluble fullerene that reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C3 has not been evaluated as a neuroprotective agent in a Parkinson model in vivo., Methods: Macaque fascicularis monkeys were used in a double-blind, placebo-controlled study design. MPTP-lesioned primates were given systemic C3 (n = 8) or placebo (n = 7) for 2 months starting 1 week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated nonhuman primate rating scale, kinematic analyses of peak upper extremity velocity, positron emission tomography imaging of 6-[(18) F]fluorodopa (FD; reflects dopa decarboxylase) and [(11) C]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), ex vivo quantification of striatal dopamine, and stereologic counts of tyrosine hydroxylase-immunostained neurons in substantia nigra., Results: After 2 months, C3 -treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C3 -treated animals developed any toxicity., Interpretation: Systemic treatment with C3 reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C3 as a promising therapeutic agent for Parkinson disease., (© 2014 American Neurological Association.)
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- 2014
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18. Spatial reorganization of putaminal dopamine D2-like receptors in cranial and hand dystonia.
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Black KJ, Snyder AZ, Mink JW, Tolia VN, Revilla FJ, Moerlein SM, and Perlmutter JS
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- Adult, Aged, Dystonia diagnostic imaging, Dystonia pathology, Female, Fluorine Radioisotopes, Hand diagnostic imaging, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography, Putamen diagnostic imaging, Putamen metabolism, Putamen pathology, Skull diagnostic imaging, Skull pathology, Spiperone, Dystonia metabolism, Hand pathology, Receptors, Dopamine D2 metabolism, Skull metabolism
- Abstract
The putamen has a somatotopic organization of neurons identified by correspondence of firing rates with selected body part movements, as well as by complex, but organized, differential cortical projections onto putamen. In isolated focal dystonia, whole putaminal binding of dopamine D2-like receptor radioligands is quantitatively decreased, but it has not been known whether selected parts of the putamen are differentially affected depending upon the body part affected by dystonia. The radioligand [(18)F]spiperone binds predominantly to D2-like receptors in striatum. We hypothesized that the spatial location of [(18)F]spiperone binding within the putamen would differ in patients with dystonia limited to the hand versus the face, and we tested that hypothesis using positron emission tomography and magnetic resonance imaging. To address statistical and methodological concerns, we chose a straightforward but robust image analysis method. An automated algorithm located the peak location of [(18)F]spiperone binding within the striatum, relative to a brain atlas, in each of 14 patients with cranial dystonia and 8 patients with hand dystonia. The mean (left and right) |x|, y, and z coordinates of peak striatal binding for each patient were compared between groups by t test. The location of peak [(18)F]spiperone binding within the putamen differed significantly between groups (cranial dystonia z
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- 2014
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19. Striatal dopamine D1-like receptor binding is unchanged in primary focal dystonia.
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Karimi M, Moerlein SM, Videen TO, Su Y, Flores HP, and Perlmutter JS
- Subjects
- Adult, Aged, Benzazepines pharmacokinetics, Benzofurans pharmacokinetics, Dystonic Disorders diagnostic imaging, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography, Corpus Striatum diagnostic imaging, Corpus Striatum metabolism, Dystonic Disorders pathology, Receptors, Dopamine D1 metabolism
- Abstract
Background: Multiple studies have demonstrated decreases in striatal D2-like (D2, D3) radioligand binding in primary focal dystonias. Although most investigations have focused on D2-specific receptors (D2R), a recent study suggests that the decreased D2-like binding may be due to a D3-specific (D3R) abnormality. However, only limited data exist on the role of D1-specific receptors (D1R) and the D1R-mediated pathways within basal ganglia in dystonia. Metabolic positron emission tomography (PET) data in primary generalized dystonia suggest resting state over activity in the D1R-mediated direct pathway, leading to excessive disinhibition of motor cortical areas. This work investigated whether striatal D1-like receptors are affected in primary focal dystonias., Methods: Striatal-specific (caudate and putamen) binding of the D1-like radioligand [(11)C]NNC 112 was measured using PET in 19 patients with primary focal dystonia (cranial, cervical, or arm) and 18 controls., Results: No statistically significant difference was detected in striatal D1-like binding between the two groups. The study had 91% power to detect a 20% difference, indicating that false-negative results were unlikely., Conclusions: Because [(11)C]NNC 112 has high affinity for D1-like receptors, very low affinity for D2-like receptors, and minimal sensitivity to endogenous dopamine levels, we conclude that D1-like receptor binding is not impaired in these primary focal dystonias., (© 2013 Movement Disorder Society.)
- Published
- 2013
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20. A comparison of D2 receptor specific binding in obese and normal-weight individuals using PET with (N-[(11)C]methyl)benperidol.
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Eisenstein SA, Antenor-Dorsey JA, Gredysa DM, Koller JM, Bihun EC, Ranck SA, Arbeláez AM, Klein S, Perlmutter JS, Moerlein SM, Black KJ, and Hershey T
- Subjects
- Adult, Age Factors, Benperidol administration & dosage, Benperidol analogs & derivatives, Body Mass Index, Brain diagnostic imaging, Brain metabolism, Case-Control Studies, Female, Humans, Male, Obesity diagnostic imaging, Obesity etiology, Organ Specificity, Positron-Emission Tomography, Obesity metabolism, Receptors, Dopamine D2 metabolism
- Abstract
Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to nonobese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R-selective radioligand (N-[(11)C] methyl)benperidol ([(11)C]NMB), which is nondisplaceable by endogenous dopamine, to estimate D2R specific binding (BPND) and its relationship to body mass index (BMI) and age in 15 normal-weight (mean BMI = 22.6 kg/m(2)) and 15 obese (mean BMI = 40.3 kg/m(2)) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BPND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BPND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal-weight and obese groups. BMI values did not correlate with D2R BPND . Age was negatively correlated with putamen D2R BPND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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21. Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques.
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Brown CA, Karimi MK, Tian L, Flores H, Su Y, Tabbal SD, Loftin SK, Moerlein SM, and Perlmutter JS
- Subjects
- Animals, Carbon Isotopes, Disease Models, Animal, Fluorodeoxyglucose F18, MPTP Poisoning diagnostic imaging, Macaca mulatta, Magnetic Resonance Imaging, Male, Substantia Nigra diagnostic imaging, Tetrabenazine analogs & derivatives, MPTP Poisoning pathology, Mesencephalon pathology, Neurons physiology, Positron-Emission Tomography, Substantia Nigra pathology
- Abstract
Objective: Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates., Methods: Presynaptic PET tracers 6-[(18)F]-fluorodopa (FD), [(11)C]-2β-methoxy-3β-4-fluorophenyltropane (CFT), and [(11)C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration., Results: We found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R(2) = 0.77, 0.53, respectively, p < 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (rs = -0.77, -0.71, respectively, p < 0.001), but FD uptake did not., Interpretation: Our findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function., (© 2013 American Neurological Association.)
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- 2013
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22. Validation of nigrostriatal positron emission tomography measures: critical limits.
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Karimi M, Tian L, Brown CA, Flores HP, Loftin SK, Videen TO, Moerlein SM, and Perlmutter JS
- Subjects
- Animals, Cocaine analogs & derivatives, Corpus Striatum diagnostic imaging, Disease Models, Animal, Fluorodeoxyglucose F18, MPTP Poisoning diagnostic imaging, Macaca mulatta, Magnetic Resonance Imaging, Male, Positron-Emission Tomography, Protein Binding drug effects, Radiopharmaceuticals, Reproducibility of Results, Substantia Nigra diagnostic imaging, Tetrabenazine analogs & derivatives, Corpus Striatum pathology, MPTP Poisoning pathology, Substantia Nigra pathology
- Abstract
Objective: Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys., Methods: Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells., Results: Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001)., Interpretation: Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury., (Copyright © 2013 American Neurological Association.)
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- 2013
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23. Characterization of extrastriatal D2 in vivo specific binding of [¹⁸F](N-methyl)benperidol using PET.
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Eisenstein SA, Koller JM, Piccirillo M, Kim A, Antenor-Dorsey JA, Videen TO, Snyder AZ, Karimi M, Moerlein SM, Black KJ, Perlmutter JS, and Hershey T
- Subjects
- Adult, Aged, Aged, 80 and over, Benperidol analysis, Cerebellum diagnostic imaging, Cerebral Cortex diagnostic imaging, Corpus Striatum diagnostic imaging, Dopamine Antagonists pharmacology, Dopamine D2 Receptor Antagonists, Female, Fluorine Radioisotopes analysis, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Organ Specificity, Benperidol analogs & derivatives, Brain diagnostic imaging, Positron-Emission Tomography, Receptors, Dopamine D2 metabolism
- Abstract
PET imaging studies of the role of the dopamine D2 receptor family in movement and neuropsychiatric disorders are limited by the use of radioligands that have near-equal affinities for D2 and D3 receptor subtypes and are susceptible to competition with endogenous dopamine. By contrast, the radioligand [¹⁸F]N-methylbenperidol ([¹⁸F]NMB) has high selectivity and affinity for the D2 receptor subtype (D2R) and is not sensitive to endogenous dopamine. Although [¹⁸F]NMB has high binding levels in striatum, its utility for measuring D2R in extrastriatal regions is unknown. A composite MR-PET image was constructed across 14 healthy adult participants representing average NMB uptake 60 to 120 min after [¹⁸F]NMB injection. Regional peak radioactivity was identified using a peak-finding algorithm. FreeSurfer and manual tracing identified a priori regions of interest (ROI) on each individual's MR image and tissue activity curves were extracted from coregistered PET images. [¹⁸F]NMB binding potentials (BP(ND) s) were calculated using the Logan graphical method with cerebellum as reference region. In eight unique participants, extrastriatal BP(ND) estimates were compared between Logan graphical methods and a three-compartment kinetic tracer model. Radioactivity and BP(ND) levels were highest in striatum, lower in extrastriatal subcortical regions, and lowest in cortical regions relative to cerebellum. Age negatively correlated with striatal BP(ND) s. BP(ND) estimates for extrastriatal ROIs were highly correlated across kinetic and graphical methods. Our findings indicate that PET with [¹⁸F]NMB measures specific binding in extrastriatal regions, making it a viable radioligand to study extrastriatal D2R levels in healthy and diseased states., (Copyright © 2012 Wiley Periodicals, Inc.)
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- 2012
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24. Dopamine pathway loss in nucleus accumbens and ventral tegmental area predicts apathetic behavior in MPTP-lesioned monkeys.
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Brown CA, Campbell MC, Karimi M, Tabbal SD, Loftin SK, Tian LL, Moerlein SM, and Perlmutter JS
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- Animals, MPTP Poisoning diagnostic imaging, MPTP Poisoning psychology, Macaca fascicularis, Macaca nemestrina, Male, Neural Pathways pathology, Nucleus Accumbens diagnostic imaging, Predictive Value of Tests, Radionuclide Imaging, Ventral Tegmental Area diagnostic imaging, Apathy physiology, Dopaminergic Neurons pathology, MPTP Poisoning pathology, Nucleus Accumbens pathology, Ventral Tegmental Area pathology
- Abstract
Apathy, primarily defined as a lack of motivation, commonly occurs in people with Parkinson disease (PD). Although dysfunction of basal ganglia pathways may contribute to apathy, the role of dopamine remains largely unknown. We investigated the role of dopaminergic pathways in the manifestation of apathetic behaviors by measuring the effects of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on monkeys' willingness to attempt goal directed behaviors, distinct from their ability to perform tasks. Fifteen macaques received variable doses of MPTP, had PET scans with [(11)C]-dihydrotetrabenazine (DTBZ), [(11)C]-2β-3β-4-fluorophenyltropane (CFT), and [(18)F]-fluorodopa (FD) and performed tasks to assess apathetic behaviors and motor impairment. At 8 weeks post-MPTP, primates were euthanized and stereological cell counts and dopamine measurements were done. Apathy scores were compared to motor scores, in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with DTBZ (r(S) = -0.85), CFT (r(S) = -0.87), and FD (r(S) = -0.85) specific uptake in nucleus accumbens (NAcc,) and dopaminergic cell counts in ventral tegmental area (VTA, r(S) = -0.80). Dopaminergic cell loss in VTA provided significant predictive power for apathy scores after controlling for the influence of cell loss in SN. Additionally, forward step-wise regression analyses indicated that neuropathological changes in the VTA-NAcc pathway predict apathetic behavior better than motor impairment or neuropathological changes in the nigrostriatal network. Our findings suggest that dopaminergic dysfunction within the VTA-NAcc pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates. Similar changes in people with PD may contribute to apathy., (Copyright © 2012 Elsevier Inc. All rights reserved.)
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- 2012
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25. Reduced uptake of FDOPA PET in end-stage liver disease with elevated manganese levels.
- Author
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Criswell SR, Perlmutter JS, Crippin JS, Videen TO, Moerlein SM, Flores HP, Birke AM, and Racette BA
- Subjects
- Caudate Nucleus diagnostic imaging, Ceruloplasmin metabolism, Dihydroxyphenylalanine pharmacokinetics, Hepatitis B complications, Humans, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Liver Cirrhosis, Alcoholic complications, Magnetic Resonance Imaging, Male, Middle Aged, Parkinson Disease diagnostic imaging, Putamen diagnostic imaging, Radionuclide Imaging, Dihydroxyphenylalanine analogs & derivatives, End Stage Liver Disease diagnostic imaging, End Stage Liver Disease metabolism, Manganese metabolism, Radiopharmaceuticals pharmacokinetics
- Abstract
Objective: To investigate whether manganese toxicity secondary to end-state liver disease is associated with nigrastriatal dysfunction as measured by 6-[(18)F]fluoro-L-DOPA (FDOPA) positron emission tomographic (PET) imaging., Design: Observational case report., Setting: The Movement Disorder Center at Washington University, St Louis, Missouri., Patient: An individual with manganese toxicity secondary to end-stage liver disease. His FDOPA PET was compared with those of 10 idiopathic Parkinson disease patients and 10 age- and sex-matched healthy controls., Main Outcome Measure: The average estimated net FDOPA uptake by Patlak graphical analysis for caudate, anterior putamen, and posterior putamen., Results: The FDOPA uptake for the patient with secondary manganese toxicity was reduced across all regions by more than 2 SDs compared with healthy controls: caudate (reduced 24.7%), anterior putamen (28.0%), and posterior putamen (29.3%). The ratio of uptake between the caudate/posterior putamen was 0.99 and was different from that of idiopathic Parkinson disease patients, in whom the greatest reduction of FDOPA was in the posterior putamen (mean [SD] ratio, 1.65 [0.41])., Conclusions: Reduce striatal uptake of FDOPA uptake indicates dysfunction of the nigrostriatal pathways in manganese toxicity secondary to end-stage liver disease. The pattern of striatal involvement with equal reduction of FDOPA uptake in the caudate compared with posterior putamen appears different from those previously reported in individuals with occupational manganese toxicity and idiopathic Parkinson disease and may be specific to manganese toxicity secondary to end-stage liver disease.
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- 2012
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26. Decreased striatal dopamine receptor binding in primary focal dystonia: a D2 or D3 defect?
- Author
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Karimi M, Moerlein SM, Videen TO, Luedtke RR, Taylor M, Mach RH, and Perlmutter JS
- Subjects
- Adult, Corpus Striatum diagnostic imaging, Dystonic Disorders diagnostic imaging, Female, Fluorine Radioisotopes, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography, Protein Binding drug effects, Radiography, Corpus Striatum metabolism, Dystonic Disorders pathology, Receptors, Dopamine D2 metabolism
- Abstract
Dystonia is an involuntary movement disorder characterized by repetitive patterned or sustained muscle contractions causing twisting or abnormal postures. Several lines of evidence suggest that abnormalities of dopaminergic pathways contribute to the pathophysiology of dystonia. In particular, dysfunction of D2-like receptors that mediate function of the indirect pathway in the basal ganglia may play a key role. We have demonstrated with positron emission tomography that patients with primary focal cranial or hand dystonia have reduced putamenal specific binding of [(18)F]spiperone, a nonselective D2-like radioligand with nearly equal affinity for serotonergic 5-HT(2A) sites. We then repeated the study with [(18)F]N-methyl-benperidol (NMB), a more selective D2-like receptor radioligand with minimal affinity for 5-HT(2A). Surprisingly, there was no decrease in NMB binding in the putamen of subjects with dystonia. Our findings excluded reductions of putamenal uptake greater than 20% with 95% confidence intervals. The analysis of the in vitro selectivity of NMB and spiperone demonstrated that NMB was highly selective for D2 receptors relative to D3 receptors (200-fold difference in affinity), whereas spiperone has similar affinity for all three of the D2-like receptor subtypes. These findings when coupled with other literature suggest that a defect in D3, rather than D2, receptor expression may be associated with primary focal dystonia., (Copyright © 2010 Movement Disorder Society.)
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- 2011
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27. Radiation dosimetry of N-([11C]methyl)benperidol as determined by whole-body PET imaging of primates.
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Antenor-Dorsey JA, Laforest R, Moerlein SM, Videen TO, and Perlmutter JS
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- Animals, Benperidol administration & dosage, Benperidol pharmacokinetics, Brain diagnostic imaging, Brain metabolism, Female, Heart diagnostic imaging, Injections, Intravenous, Liver diagnostic imaging, Liver metabolism, Male, Models, Animal, Myocardium metabolism, Papio, Positron-Emission Tomography, Receptors, Dopamine D2 metabolism, Tissue Distribution, Whole-Body Irradiation, Benperidol analogs & derivatives
- Abstract
Purpose: N-([(11)C]methyl)benperidol ([(11)C]NMB) can be used for positron emission tomography (PET) measurements of D(2)-like dopamine receptor binding in vivo. We report the absorbed radiation dosimetry of i.v.-administered (11)C-NMB, a critical step before applying this radioligand to imaging studies in humans., Materials and Methods: Whole-body PET imaging with a CTI/Siemens ECAT 953B scanner was done in a male and a female baboon. After i.v. injection of 444-1221 MBq of (11)C-NMB, sequential images taken from the head to the pelvis were collected for 3 h. Volumes of interest (VOIs) were identified that entirely encompassed small organs (whole brain, striatum, eyes, and myocardium). Large organs (liver, lungs, kidneys, lower large intestine, and urinary bladder) were sampled by drawing representative regions within the organ volume. Time-activity curves for each VOI were extracted from the PET, and organ residence times were calculated by analytical integration of a multi-exponential fit of the time-activity curves. Human radiation doses were estimated using OLINDA/EXM 1.0 and the standard human model., Results: Highest retention was observed in the blood and liver, each with total residence times of 1.5 min. The highest absorbed radiation doses were to the heart (10.5 μGy/MBq) [DOSAGE ERROR CORRECTED] and kidney (9.19 μGy/MBq), [DOSAGE ERROR CORRECTED] making these the critical organs for [(11)C]NMB. A heart absorption of 50 mGy would result from an injected dose of 4,762 MBq [(11)C]NMB., Conclusions: Thus, this study suggests that up to 4,762 MBq of [(11)C]NMB can be safely administered to human subjects for PET studies. Total body dose and effective dose for [(11)C]NMB are 2.82 μGy/MBq [DOSAGE ERROR CORRECTED] and 3.7 mSv/kBq, respectively.
- Published
- 2008
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28. Validation of the reference tissue model for estimation of dopaminergic D2-like receptor binding with [18F](N-methyl)benperidol in humans.
- Author
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Antenor-Dorsey JA, Markham J, Moerlein SM, Videen TO, and Perlmutter JS
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- Adult, Benperidol blood, Benperidol chemistry, Benperidol pharmacokinetics, Calibration, Caudate Nucleus diagnostic imaging, Data Interpretation, Statistical, Female, Fluorine Radioisotopes blood, Fluorine Radioisotopes chemistry, Fluorine Radioisotopes pharmacokinetics, Humans, Least-Squares Analysis, Male, Metabolic Clearance Rate, Middle Aged, Models, Theoretical, Positron-Emission Tomography methods, Positron-Emission Tomography standards, Putamen diagnostic imaging, Radial Artery diagnostic imaging, Radioligand Assay methods, Radiopharmaceuticals blood, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Receptors, Dopamine D2 analysis, Reference Standards, Benperidol analogs & derivatives, Radioligand Assay standards, Receptors, Dopamine D2 chemistry, Signal Processing, Computer-Assisted, Subtraction Technique
- Abstract
Positron emission tomography measurements of dopaminergic D2-like receptors may provide important insights into disorders such as Parkinson's disease, schizophrenia, dystonia and Tourette's syndrome. The positron emission tomography (PET) radioligand [18F](N-methyl)benperidol ([18F]NMB) has high affinity and selectivity for D2-like receptors and is not displaced by endogenous dopamine. The goal of this study is to evaluate the use of a graphical method utilizing a reference tissue region for [18F]-NMB PET analysis by comparisons to an explicit three-compartment tracer kinetic model and graphical method that use arterial blood measurements. We estimated binding potential (BP) in the caudate and putamen using all three methods in 16 humans and found that the three-compartment tracer kinetic method provided the highest BP estimates while the graphical method using a reference region yielded the lowest estimates (P<.0001 by repeated-measures ANOVA). However, the three methods yielded highly correlated BP estimates for the two regions of interest. We conclude that the graphical method using a reference region still provides a useful estimate of BP comparable to methods using arterial blood sampling, especially since the reference region method is less invasive and computationally more straightforward, thereby simplifying these measurements.
- Published
- 2008
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29. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced acute transient dystonia in monkeys associated with low striatal dopamine.
- Author
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Tabbal SD, Mink JW, Antenor JA, Carl JL, Moerlein SM, and Perlmutter JS
- Subjects
- Animals, Behavior, Animal drug effects, Brain Chemistry drug effects, Cell Count, Corpus Striatum diagnostic imaging, Corpus Striatum drug effects, Corpus Striatum pathology, Dose-Response Relationship, Drug, Dystonic Disorders diagnostic imaging, Macaca fascicularis, Macaca nemestrina, Male, Positron-Emission Tomography methods, Time Factors, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Corpus Striatum metabolism, Dopamine metabolism, Dystonic Disorders chemically induced, Dystonic Disorders pathology
- Abstract
Unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in baboons produces transient contralateral dystonia lasting 2-3 weeks followed by chronic hemiparkinsonism. We now extend this model to Macaca nemestrina and Macaca fascicularis. MPTP was infused unilaterally into the internal carotid artery of two M. nemestrina and 11 M. fascicularis. Effects were assessed with blinded clinical ratings of dystonia and Parkinsonism; [18F]-6-fluoro-DOPA (FDOPA) positron emission tomography; and postmortem measurements of striatal dopamine content. In two M. nemestrina, MPTP 0.4 mg/kg intracarotid produced acute dystonia within 24 h then chronic Parkinsonism starting 3 weeks later. In three M. fascicularis, MPTP 0.4 mg/kg produced acute dystonia within 3-8 h but two others died from large hemispheric infarcts within 1 day. A much lower dose, MPTP 0.1 mg/kg produced no clinical manifestations (n=1), whereas MPTP 0.25 mg/kg produced consistent transient dystonia and ipsiversive turning within 1-3 days followed by chronic Parkinsonism at 3 weeks (n=5). One week after MPTP, striatal FDOPA uptake decreased an average of 69% in M. nemestrina (0.4 mg/kg); and decreased an average of 70+/-21% in M. fascicularis (0.25 mg/kg). Striatal dopamine was reduced an average 66% in the first day (n=2) during acute dystonia, 98% at 3 days (n=1) and 99%+/-2.3% at 2-4 months (n=5). M. nemestrina had a clinical response similar to baboons whereas M. fascicularis seemed more sensitive to MPTP. These findings extend the model of MPTP-induced transient dystonia followed by chronic hemiparkinsonism to M. nemestrina and M. fascicularis and demonstrate that the early dystonic phase is accompanied by striatal dopamine deficiency.
- Published
- 2006
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30. [18F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies.
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Racette BA, Good L, Antenor JA, McGee-Minnich L, Moerlein SM, Videen TO, and Perlmutter JS
- Subjects
- Adult, Aged, Aged, 80 and over, Consanguinity, Ethnicity, Family Health, Female, Fluorine Radioisotopes, Genetic Predisposition to Disease genetics, Genotype, Humans, Lod Score, Male, Middle Aged, Pedigree, Phenotype, Dihydroxyphenylalanine analogs & derivatives, Genetic Linkage, Parkinson Disease diagnosis, Parkinson Disease genetics, Positron-Emission Tomography methods
- Abstract
Parkinson disease (PD) is a late onset disorder with age-dependent penetrance that may confound genetic studies, since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at-risk subjects. Positron emission tomography (PET) measurements of 6-[18F]fluorodopa ([18F]FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed [18F]FDOPA PET in 11 members of a large, multi-incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal [18F]FDOPA posterior putamen uptake was defined as less than 3 standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to "PET definite PD." The remainder had normal PETs. The average maximum LOD score with the pre-PET was 6.14 +/- 0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36 +/- 1.23. The [18F]FDOPA PET endophenotype permits phenoconversion in multi-incident PD families and may increase LOD score accuracy and power of an informative pedigree., (Copyright 2006 Wiley-Liss, Inc.)
- Published
- 2006
- Full Text
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31. [18F]FDOPA PET and clinical features in parkinsonism due to manganism.
- Author
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Racette BA, Antenor JA, McGee-Minnich L, Moerlein SM, Videen TO, Kotagal V, and Perlmutter JS
- Subjects
- Adult, Antiparkinson Agents therapeutic use, Carbidopa therapeutic use, Drug Combinations, Female, Gait, Humans, Levodopa therapeutic use, Magnetic Resonance Imaging, Middle Aged, Parkinson Disease drug therapy, Brain metabolism, Fluorodeoxyglucose F18, Manganese Poisoning blood, Manganese Poisoning complications, Parkinson Disease etiology, Parkinson Disease pathology, Positron-Emission Tomography, Radiopharmaceuticals
- Abstract
Manganese exposure reportedly causes a clinically and pathophysiologically distinct syndrome from idiopathic Parkinson's disease (PD). We describe the clinical features and results of positron emission tomography with 6-[18F]fluorodopa ([18F]FDOPA PET) of a patient with parkinsonism occurring in the setting of elevated blood manganese. The patient developed parkinsonism associated with elevated serum manganese from hepatic dysfunction. [18F]FDOPA PET demonstrated relatively symmetric and severely reduced [18F]FDOPA levels in the posterior putamen compared to controls. The globus pallidum interna had increased signal on T1-weighted magnetic resonance imaging (MRI) images. We conclude that elevated manganese exposure may be associated with reduced striatal [18F]FDOPA uptake, and MRI may reveal selective abnormality within the internal segment of the pallidum. This case suggests that the clinical and pathophysiological features of manganese-associated parkinsonism may overlap with that of PD., (Copyright 2005 Movement Disorder Society.)
- Published
- 2005
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32. Decreased hippocampal 5-HT(2A) receptor binding in older depressed patients using [18F]altanserin positron emission tomography.
- Author
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Sheline YI, Mintun MA, Barch DM, Wilkins C, Snyder AZ, and Moerlein SM
- Subjects
- Aged, Aged, 80 and over, Brain Mapping, Case-Control Studies, Depressive Disorder classification, Female, Fluorine Radioisotopes pharmacokinetics, Humans, Male, Middle Aged, Protein Binding physiology, Depressive Disorder metabolism, Hippocampus diagnostic imaging, Ketanserin analogs & derivatives, Ketanserin pharmacokinetics, Positron-Emission Tomography methods, Receptor, Serotonin, 5-HT2A metabolism
- Abstract
Serotonin receptor changes have been associated with the pathophysiology and treatment of major depression. Only one other study has investigated serotonin receptor changes in older depressed patients. We used positron emission tomography (PET) and [18F]altanserin, a ligand with high affinity for the 5-HT(2A) receptor, to examine the relationship between 5-HT(2A) receptor density and depression. Depressed subjects (n = 16), age > 50 years, were recruited as part of a larger study. Older depressed subjects consisted of early-onset recurrent depression (EORD, n = 11) and late-onset depression (LOD, n = 5). An age-matched control group (n = 9) was also recruited. All subjects were right-handed, nonsmokers and antidepressant-free. Regions of interest were determined on a summed MPRAGE scan transformed into Talairach space and coregistered with the PET images. Depressed subjects had less hippocampal 5-HT(2A) receptor binding than controls (p = 0.05). No significant differences in receptor binding were found between EORD and LOD subjects. Depressed subjects not previously treated for depression (n = 6) had less hippocampal 5-HT(2A) receptor binding (p = 0.04) than previously treated subjects (n = 10). It may be that prior medication treatment provides a compensatory upregulation of the 5-HT(2A) receptor.
- Published
- 2004
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33. Pathophysiology of parkinsonism due to hydrocephalus.
- Author
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Racette BA, Esper GJ, Antenor J, Black KJ, Burkey A, Moerlein SM, Videen TO, Kotagal V, Ojemann JG, and Perlmutter JS
- Subjects
- Adult, Antiparkinson Agents therapeutic use, Brain Mapping, Carbidopa therapeutic use, Caudate Nucleus physiopathology, Cerebral Ventricles physiopathology, Drug Combinations, Equipment Failure, Humans, Hydrocephalus physiopathology, Hydrocephalus surgery, Hypokinesia drug therapy, Hypokinesia physiopathology, Levodopa therapeutic use, Magnetic Resonance Imaging, Male, Neurologic Examination, Parkinsonian Disorders drug therapy, Positron-Emission Tomography, Postoperative Complications drug therapy, Putamen physiopathology, Hydrocephalus complications, Parkinsonian Disorders physiopathology, Postoperative Complications physiopathology, Ventriculoperitoneal Shunt
- Abstract
We report a patient with hydrocephalus who developed levodopa responsive parkinsonism and severe bradyphrenia associated with shunt malfunction and revision. Magnetic resonance imaging revealed periaqueductal edema involving medial substantia nigra. [18F]dopa positron emission tomography demonstrated reduced uptake in the caudate and putamen with relative sparing of the posterior putamen. Hydrocephalus associated with shunt malfunction can cause a distinct parkinsonian syndrome with greater dysfunction of projections from the medial substantia nigra to anterior striatum than in idiopathic Parkinson's disease.
- Published
- 2004
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34. Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography.
- Author
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Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, and Snyder AZ
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Case-Control Studies, Depressive Disorder, Major diagnostic imaging, Female, Fluorine Radioisotopes, Hippocampus diagnostic imaging, Humans, Male, Middle Aged, Depressive Disorder, Major metabolism, Hippocampus metabolism, Ketanserin analogs & derivatives, Receptor, Serotonin, 5-HT2A metabolism, Tomography, Emission-Computed methods
- Abstract
Background: Serotonin 5-HT(2A) receptors play an important role in the regulation of many functions that are disturbed in patients with major depressive disorder. Postmortem and positron emission tomography studies have reported both increased and decreased 5-HT(2A) receptor binding in different limbic and paralimbic regions., Methods: We conducted a quantitative 5-HT(2A) receptor binding study using positron emission tomography and [(18)F]altanserin of four regions hypothesized to have altered levels of 5-HT(2A) receptors in major depressive disorder. Using a four-compartment model, the 5-HT(2A) receptor distribution was estimated by calculating the regional [(18)F]altanserin k(3)/k(4) ratio in which k(3) is the rate of binding to the receptor and k(4) is the rate of dissociation from the receptor. Forty-six antidepressant-free patients with major depressive disorder and 29 healthy control subjects were enrolled., Results: 5-HT(2A) receptor binding in the hippocampus was reduced by 29% in depressed subjects (p =.004). In other regions, 5-HT(2A) receptor binding was decreased (averaging 15%) but not significantly. Both groups had similar age-dependent decreases in 5-HT(2A) receptors throughout all brain regions., Conclusions: Altered serotoninergic function in the hippocampus is likely involved in the disturbances of mood regulation in major depressive disorder, although the specific role of the 5-HT(2A) receptor changes is still unclear.
- Published
- 2004
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35. Robotic preparation of Sodium Acetate C 11 Injection for use in clinical PET.
- Author
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Moerlein SM, Gaehle GG, and Welch MJ
- Subjects
- Carbon Isotopes administration & dosage, Equipment Design, Humans, Injections, Sodium Acetate administration & dosage, Software, Tomography, Emission-Computed, Isotope Labeling instrumentation, Isotope Labeling methods, Radiopharmaceuticals chemical synthesis, Robotics instrumentation, Robotics methods
- Abstract
Sodium Acetate C 11 Injection is a radiopharmaceutical commonly used for clinical studies with positron emission tomography (PET). We have designed a fully-automated robotic system for the compounding of this 20-minute half-lived tracer in the clinical setting. The system is comprised of five modular workstations that are configured in a flexible manner to accommodate all of the steps in the production of the labeled drug. The Trapping Station isolates cyclotron-produced [11C]CO(2) gas from the target and directs carbonation of methylmagnesium Grignard in diethyl ether. The Heating Station hydrolyzes the intermediate, and removes ether and unreacted [11C]CO(2) from the mixture. The Extraction Station removes ionic and organic contaminants from the drug using solid-phase extraction (AG 11A8 and C18 resin). The Filtration Station sterilizes the radiopharmaceutical, and tests membrane patency post filtration. The Assay Station measures the weight and radioactivity content of the Final Product Container, facilitating calculation of activity concentration in a remote manner. Rapid quality control methodology has also been developed that is suitable for pre-release analysis of the drug product. For a 7.5 min irradiation with a 40 microA proton beam, 223-300 mCi of Acetate C 11 Injection with purity meeting USP standards is produced within 23 min. This robotic system is a reliable method for producing Sodium Acetate C 11 Injection, USP in the clinical setting with minimal personnel exposure. Moreover, its design flexibility permits synthesis of additional (11)C- or (18)F-labeled PET tracers within the same shielded hot cell.
- Published
- 2002
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36. Greater loss of 5-HT(2A) receptors in midlife than in late life.
- Author
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Sheline YI, Mintun MA, Moerlein SM, and Snyder AZ
- Subjects
- Adult, Age Factors, Aged, Aging physiology, Brain diagnostic imaging, Brain physiology, Female, Frontal Lobe chemistry, Frontal Lobe metabolism, Hippocampus chemistry, Hippocampus metabolism, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Occipital Lobe chemistry, Occipital Lobe metabolism, Prefrontal Cortex chemistry, Prefrontal Cortex metabolism, Receptor, Serotonin, 5-HT2A, Receptors, Serotonin metabolism, Tomography, Emission-Computed, Aging metabolism, Brain metabolism, Receptors, Serotonin analysis
- Abstract
Objective: Earlier work has shown markedly lower density of serotonin 2A (5-HT(2A)) receptors in elderly subjects than in young healthy subjects. In this study the authors used positron emission tomography (PET) and [(18)F]altanserin, a ligand with high affinity for the 5-HT(2A) receptor, to examine the relationship between 5-HT(2A) receptor density and age in more detail., Method: The 22 subjects ranged in age from 21 to 69 years (mean=43.4, SD=13.3) and were healthy comparison subjects in a study of depression. Regions of interest were determined on magnetic resonance images and were transferred to coregistered PET data. The data were derived from dynamic PET scanning and arterial sampling with resulting plasma activity data corrected for labeled metabolites. Compartmental modeling was used to estimate the radioligand distribution volume. By comparing the distribution volume (DV) of different regions to the cerebellum distribution volume, DV(ratio)-1, which is proportional to the binding potential, was calculated., Results: The decrease in 5-HT(2A) binding was not linear but on average was approximately 17% per decade from age 20. The correlations between age and 5-HT(2A) DV(ratio)-1 were significant for the global measure and for the medial gyrus rectus, anterior cingulate, posterior medial prefrontal cortex, hippocampus, and occipital cortex. Most of the fall off in receptor binding occurred up through midlife, and there was less decrease in late life. There were no decreases in regional brain volumes of corresponding magnitudes., Conclusions: 5-HT(2A) receptor binding decreases dramatically in a variety of brain regions up through midlife.
- Published
- 2002
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37. Welding-related parkinsonism: clinical features, treatment, and pathophysiology.
- Author
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Racette BA, McGee-Minnich L, Moerlein SM, Mink JW, Videen TO, and Perlmutter JS
- Subjects
- Adult, Age of Onset, Aged, Case-Control Studies, Dihydroxyphenylalanine analogs & derivatives, Female, Humans, Male, Manganese adverse effects, Middle Aged, Neostriatum pathology, Occupational Diseases pathology, Occupational Diseases therapy, Occupational Exposure, Parkinson Disease pathology, Parkinson Disease therapy, Risk Factors, Tomography, Emission-Computed, Occupational Diseases epidemiology, Parkinson Disease epidemiology, Welding
- Abstract
Objective: To determine whether welding-related parkinsonism differs from idiopathic PD., Background: Welding is considered a cause of parkinsonism, but little information is available about the clinical features exhibited by patients or whether this is a distinct disorder., Methods: The authors performed a case-control study that compared the clinical features of 15 career welders, who were ascertained through an academic movement disorders center and compared to two control groups with idiopathic PD. One control group was ascertained sequentially to compare the frequency of clinical features, and the second control group was sex- and age-matched to compare the frequency of motor fluctuations., Results: Welders were exposed to a mean of 47,144 welding hours. Welders had a younger age at onset (46 years) of PD compared with sequentially ascertained controls (63 years; p < 0.0001). There was no difference in frequency of tremor, bradykinesia, rigidity, asymmetric onset, postural instability, family history, clinical depression, dementia, or drug-induced psychosis between the welders and the two control groups. All treated welders responded to levodopa. Motor fluctuations and dyskinesias occurred at a similar frequency in welders and the two control groups. PET with 6-[18F]fluorodopa obtained in two of the welders showed findings typical of idiopathic PD, with greatest loss in posterior putamen., Conclusions: Parkinsonism in welders is distinguished clinically only by age at onset, suggesting welding may be a risk factor for PD. These preliminary data cannot exclude a genetic contribution to susceptibility in these exposed individuals.
- Published
- 2001
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38. PET measurements of dopaminergic pathways in the brain.
- Author
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Perlmutter JS and Moerlein SM
- Subjects
- Adrenergic Fibers metabolism, Brain Diseases diagnostic imaging, Brain Diseases metabolism, Cerebrovascular Circulation physiology, Dopamine metabolism, Dopamine Agents pharmacokinetics, Dystonia diagnostic imaging, Dystonia metabolism, Dystonia physiopathology, Humans, Levodopa pharmacokinetics, Neural Pathways diagnostic imaging, Neural Pathways metabolism, Parkinson Disease diagnostic imaging, Parkinson Disease metabolism, Parkinson Disease physiopathology, Radiopharmaceuticals, Receptors, Dopamine metabolism, Schizophrenia diagnostic imaging, Schizophrenia metabolism, Schizophrenia physiopathology, Adrenergic Fibers diagnostic imaging, Brain Diseases physiopathology, Dopamine physiology, Receptors, Dopamine physiology, Tomography, Emission-Computed
- Abstract
Positron emission tomography (PET) measurements of dopaminergic pathways have revealed several new insights into the role of dopamine in the pathophysiology and pharmacology of brain diseases such as Parkinson's disease (PD), dystonia and schizophrenia. PET studies of regional blood flow or metabolism identifies sites of regional pathology. Drug-induced changes in flow or metabolism indicate the function of dopamine-mediated pathways. Measurements of radioligand binding in vivo with PET reveals abnormalities associated with specific diseases and the actions of various drugs that affect the dopaminergic system. Finally, PET measurements of the uptake of analogues of levodopa provide clues to the function of dopamine pathways potentially important for diagnosis and treatment of disease like PD.
- Published
- 1999
39. Decreased [18F]spiperone binding in putamen in dystonia.
- Author
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Perlmutter JS, Stambuk MK, Markham J, Black KJ, McGee-Minnich L, Jankovic J, and Moerlein SM
- Subjects
- Adult, Aged, Dystonia metabolism, Female, Fluorine Radioisotopes, Handwriting, Humans, Kinetics, Male, Middle Aged, Muscle Cramp diagnostic imaging, Muscle Cramp metabolism, Muscle Cramp physiopathology, Putamen chemistry, Receptors, Dopamine D2 metabolism, Spiperone, Tomography, Emission-Computed, Dystonia diagnostic imaging, Dystonia physiopathology, Putamen diagnostic imaging, Putamen physiopathology
- Published
- 1998
40. In vivo kinetics of [18F](N-methyl)benperidol: a novel PET tracer for assessment of dopaminergic D2-like receptor binding.
- Author
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Moerlein SM, Perlmutter JS, Markham J, and Welch MJ
- Subjects
- Animals, Benperidol metabolism, Benperidol pharmacokinetics, Papio, Tomography, Emission-Computed, Benperidol analogs & derivatives, Brain metabolism, Receptors, Dopamine D2 metabolism
- Abstract
A novel D2-like receptor-binding radioligand, [18F](N-methyl)benperidol ([18F]NMB), was evaluated via positron emission tomographic (PET) imaging studies of baboons. [18F]NMB rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and striatum-to-cerebellum ratios as high as 35 were achieved after 3 hours. Pretreatment of an animal with unlabeled receptor-specific antagonists before injection of [18F]NMB confirmed that the radioligand bound specifically to central D2-like receptors in vivo, and not to S2- or D1-like receptors. Unlabeled eticlopride displaced striatal [18F]NMB in vivo, showing that D2-like binding is reversible. Receptor-binding by the radioligand was resistant to competitive displacement by synaptic dopamine, as illustrated by the lack of effect of intravenous d-amphetamine on the in vivo localization of [18F]NMB. Studies involving sequential intravenous administration of [18F]NMB, d-amphetamine, and eticlopride show that the radioligand does not undergo agonist-mediated internalization with subsequent trapping. The feasibility of applying a three-compartment non-steady state model for quantification of [18F]NMB receptor binding was demonstrated. These in vivo characteristics give [18F]NMB distinct advantages over the PET radiopharmaceuticals currently used for clinical investigation of D2-like receptor binding.
- Published
- 1997
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41. Radiation dosimetry of [18F] (N-methyl)benperidol as determined by whole-body PET imaging of primates.
- Author
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Moerlein SM, Perlmutter JS, Cutler PD, and Welch MJ
- Subjects
- Animals, Benperidol metabolism, Humans, Male, Papio, Benperidol analogs & derivatives, Dopamine Antagonists metabolism, Fluorine Radioisotopes, Radiation Dosage, Tomography, Emission-Computed
- Abstract
Radiation absorbed doses due to IV administration of [18F](N-methyl) benperidol ([18F]NMB) were estimated by whole-body PET imaging of nonhuman primates. Time-activity curves were obtained for nine compartments (striatum, eyes, heart, lungs, liver, gallbladder, intestines, kidneys, bladder) by using dynamic PET scans of three different baboons given the radiotracer. These time-activity curves were used to calculate the residence times of radioactivity in these tissues. Human absorbed dose estimates were calculated using the updated MIRDOSE 3 S values and assuming the same biodistribution. Based on an average of three studies, the critical organs were the lower large intestine, gallbladder, and liver, receiving doses of 585, 281, and 210 mrad/mCi, respectively. The brain received a dose of 13 mrad/mCi; other organs received doses between 32-77 mrad/mCi. These results indicate that up to 8.5 mCi of [18F]NMB can be safely administered to human subjects for PET studies of D2 receptor binding.
- Published
- 1997
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42. Decreased [18F]spiperone binding in putamen in idiopathic focal dystonia.
- Author
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Perlmutter JS, Stambuk MK, Markham J, Black KJ, McGee-Minnich L, Jankovic J, and Moerlein SM
- Subjects
- Adult, Aged, Basal Ganglia physiopathology, Blepharospasm pathology, Cerebrovascular Circulation, Dopamine physiology, Dystonia pathology, Facial Muscles physiopathology, Female, Fluorine Radioisotopes, Hand physiopathology, Humans, Male, Middle Aged, Nerve Tissue Proteins metabolism, Parkinson Disease physiopathology, Putamen pathology, Receptors, Dopamine D2 metabolism, Single-Blind Method, Tomography, Emission-Computed, Blepharospasm metabolism, Dystonia metabolism, Nerve Tissue Proteins deficiency, Putamen chemistry, Receptors, Dopamine D2 deficiency, Spiperone pharmacokinetics
- Abstract
In this study we have investigated the pathophysiology of two idiopathic focal dystonias: hand cramp with excessive cocontractions of agonist and antagonist hand or forearm muscles during specific tasks, such as writing, and facial dystonia manifested by involuntary eyelid spasms (blepharospasm) and lower facial and jaw spasms (oromandibular dystonia). We used positron emission tomography (PET) to measure the in vivo binding of the dopaminergic radioligand [18F]spiperone in putamen in 21 patients with these two focal dystonias and compared the findings with those from 13 normals. We measured regional cerebral blood flow and blood volume in each subject as well as the radiolabeled metabolites of [18F]spiperone in arterial blood. A stereotactic method of localization, independent of the appearance of the images, was used to identify the putamen in all of the PET images. We analyzed the PET and arterial blood data with a validated nonsteady-state tracer kinetic model representing the in vivo behavior of the radioligand. An index of binding called the combined forward rate constant was decreased by 29% in dystonics, as compared with normals (p < 0.05). There were no significant differences between dystonics and normals in regional blood flow, blood volume, nonspecific binding, permeability-surface area product of [18F]spiperone or the dissociation rate constant. These findings are consistent with a decrease of dopamine D2-like binding in putamen and are the first demonstration of a receptor abnormality in idiopathic dystonia. These results have important implications for the pathophysiology of dystonia as well as for function of the basal ganglia.
- Published
- 1997
43. Specific, reversible binding of [18F]benperidol to baboon D2 receptors: PET evaluation of an improved 18F-labeled ligand.
- Author
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Moerlein SM, Perlmutter JS, and Welch MJ
- Subjects
- Animals, Benzazepines pharmacology, Brain metabolism, Corpus Striatum drug effects, Corpus Striatum metabolism, Dopamine Antagonists pharmacology, Kinetics, Papio, Radioligand Assay, Receptors, Dopamine D2 analysis, Salicylamides pharmacology, Time Factors, Benperidol metabolism, Brain diagnostic imaging, Fluorine Radioisotopes, Receptors, Dopamine D2 metabolism, Tomography, Emission-Computed
- Abstract
[18F]Benperidol ([18F]BP), a positron-emitting analogue of the dopaminergic D2 antagonist benperidol, was evaluated as a radiopharmaceutical for use with positron emission tomography (PET). PET imaging of baboons after i.v. injection of [18F]BP indicated that the radiofluorinated ligand rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and that selective disposition was retained for over 2 h. Pretreatment of an animal with unlabeled receptor-specific antagonists prior to injection of [18F]BP confirmed that the radioligand bound specifically to central D2 receptors in vivo, and not to S2 or D1 receptors. [18F]BP bound to D2 receptors in a reversible manner; unlabeled eticlopride displaced D2 receptor-bound [18F]BP in vivo. The radioligand was metabolized in the periphery to polar metabolites which are not expected to cross the blood-brain barrier. [18F]BP has advantages over other tracers as a radiopharmaceutical for PET study of central D2 receptor activity, and can be applied for noninvasive evaluation of the interaction of unlabeled drugs with central D2 receptor sites.
- Published
- 1995
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44. First-pass extraction fraction of iodine-123 labeled perfusion tracers in living primate brain.
- Author
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Moerlein SM, Perlmutter JS, Welch MJ, and Raichle ME
- Subjects
- Animals, Brain diagnostic imaging, Papio, Perfusion, Tomography, Emission-Computed, Single-Photon, Brain metabolism, Iodine Radioisotopes pharmacokinetics, Radiopharmaceuticals pharmacokinetics
- Abstract
The cerebral extraction and retention of three radioiodinatéd SPECT perfusion tracers were measured using residue detection in a baboon. A permeability-surface area product PS' with special relevance to SPECT was calculated from the retention of tracer in the brain after 10 min. PS' differs from the traditional PS value, which is calculated from the tracer clearance curve at 2 min. The PS' values ranged from 50 to 95 mL/min/100 g, decreased in the order [123I]IMP > [123I]iodoperidol approximately [123I]HIPDM, and did not differ for specific activities of 10 MBq/mmol to 74 TBq/mmol. These radioiodinated compounds exhibited extraction characteristics superior to those of [99mTc]HMPAO but underestimated cerebral blood flow when flows were above 20-30 mL/min/100 g, underscoring the need for development of a more ideal SPECT perfusion tracer.
- Published
- 1994
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45. Automated production of oxygen-15 labeled butanol for PET measurement of regional cerebral blood flow.
- Author
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Moerlein SM, Gaehle GG, Lechner KR, Bera RK, and Welch MJ
- Subjects
- Humans, Butanols, Cerebrovascular Circulation, Isotope Labeling methods, Oxygen Radioisotopes, Tomography, Emission-Computed
- Abstract
Because [15O]butanol is the radiopharmaceutical of choice for PET studies of cerebral perfusion and neurological activation, we have developed a microprocessor-controlled radiosynthetic system for the preparation of this radiotracer in up to ten batches at a time. An IBM-compatible minicomputer was programmed to direct the reaction of molecular [15O]oxygen with tri-(n-butyl)borane bound to alumina, followed by purification of product [15O]butanol via solid phase extraction with C18 Sep-Paks and sterile filtration. Routine batch yields of over 150 mCi were achieved with a preparation turn-around time of 6.0 min. The final product had high radiochemical purity, low chemical impurity, and was sterile and apyrogenic. This radiopharmaceutical production system is reliable and suitable for tracer production in clinical PET imaging centers.
- Published
- 1993
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46. Metabolism in vitro of radioiodinated N-isopropyl-p-iodoamphetamine by isolated hepatocytes.
- Author
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Moerlein SM, Weisman RA, Beck D, Li AP, and Welch MJ
- Subjects
- Adult, Animals, Cryopreservation, Drug Evaluation, Preclinical methods, Female, Humans, Iofetamine, Liver cytology, Male, Rats, Rats, Inbred F344, Sex Factors, Solvents, Amphetamines metabolism, Iodine Radioisotopes metabolism, Liver metabolism
- Abstract
An in vitro technique for the determination of radiopharmaceutical metabolism has been developed using isolated hepatocytes. Radioiodinated N-isopropyl-p-iodoamphetamine (IMP; iofetamine, USP) was employed a model tracer in these studies because its labeled metabolites are well-characterized. Hepatocytes isolated from the rat and human produced labeled metabolites in vitro for up to 4 h in a manner similar to that reported for humans in vivo. Identical metabolites were generated by all cell types investigated, but the rate of metabolism differed (rat >> human; female > male; fresh > frozen). The utility of this methodology for the preclinical evaluation of potential radiopharmaceuticals is described.
- Published
- 1993
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47. Specific binding of 3N-(2'-[18F]fluoroethyl)benperidol to primate cerebral dopaminergic D2 receptors demonstrated in vivo by PET.
- Author
-
Moerlein SM and Perlmutter JS
- Subjects
- Animals, Basal Ganglia diagnostic imaging, Basal Ganglia drug effects, Basal Ganglia metabolism, Benperidol metabolism, Benzazepines pharmacology, Brain diagnostic imaging, Cerebellum diagnostic imaging, Cerebellum metabolism, Dopamine D2 Receptor Antagonists, Fluorine Radioisotopes, Ketanserin pharmacology, Kinetics, Papio, Receptors, Dopamine D2 drug effects, Salicylamides pharmacology, Tomography, Emission-Computed methods, Benperidol analogs & derivatives, Brain metabolism, Receptors, Dopamine D2 metabolism
- Abstract
3N-(2'-[18F]Fluoroethyl)benperidol ([18F]FEB) an 18F-labeled analogue of the D2 antagonist benperidol, was evaluated as a tracer for positron emission tomography (PET). PET imaging of a living baboon showed that the fluorinated ligand rapidly localized in vivo within D2 receptor-rich brain tissue, with selective retention lasting over 2 h after tracer injection. Pretreatment of the animal with unlabeled D2-specific antagonist eticlopride (4 mg/kg, i.v.) 1 h before [18F]FEB completely abolished the selective disposition of the radioligand, whereas the regional cerebral blood flow, blood volume and peripheral metabolism/protein binding of [18F]FEB were not changed. Tracer localization when the baboon was pretreated with unlabeled ketanserin (0.55 mg/kg, i.v.) or SCH 23390 (1.1 mg/kg, i.v.) was identical to that for the control case, indicating that the [18F]FEB did not bind to S2 of D1 receptors in vivo. [18F]FEB has advantages compared to previously used PET tracers, and may be an excellent radioligand for non-invasive study of D2 receptor binding.
- Published
- 1992
- Full Text
- View/download PDF
48. Functional recovery after coronary revascularization for chronic coronary artery disease is dependent on maintenance of oxidative metabolism.
- Author
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Gropler RJ, Geltman EM, Sampathkumaran K, Pérez JE, Moerlein SM, Sobel BE, Bergmann SR, and Siegel BA
- Subjects
- Adult, Aged, Chronic Disease, Coronary Circulation physiology, Coronary Disease therapy, Female, Glucose metabolism, Heart diagnostic imaging, Humans, Male, Middle Aged, Myocardial Revascularization, Oxidation-Reduction, Tomography, Emission-Computed, Treatment Outcome, Ventricular Function, Coronary Disease metabolism, Myocardium metabolism
- Abstract
Objectives: This study was performed to define the importance of maintenance of oxidative metabolism as a descriptor and determinant of functional recovery after revascularization in patients with left ventricular dysfunction attributable to chronic coronary artery disease., Background: Although myocardial accumulation of 18F-fluorodeoxyglucose indicates the presence of tissue that is metabolically active, it may not identify those metabolic processes required for restoration of myocardial contractility. Experimental studies suggest that, under conditions of ischemia and reperfusion, maintenance of myocardial oxidative metabolism is an important metabolic determinant of the capacity for functional recovery., Methods: In 16 patients positron emission tomography was performed to characterize myocardial perfusion (with H(2)15O), oxidative metabolism (with 11C-acetate) and utilization of glucose (with 18F-fluorodeoxyglucose). Dysfunctional but viable myocardium was differentiated from nonviable myocardium on the basis of assessments of regional function before and after coronary revascularization. To define the importance of coronary revascularization on myocardial perfusion and metabolism, tomography was repeated in 11 patients after revascularization., Results: Before revascularization, perfusion in 24 dysfunctional but viable myocardial segments and 29 nonviable segments averaged 79% and 74%, respectively, of that in 42 normal myocardial segments (both p less than 0.01). Dysfunctional but viable myocardium exhibited oxidative metabolism comparable to that in normal myocardium. In contrast, in nonviable myocardium, oxidative metabolism was only 66% of that in normal (p less than 0.01) and 69% of that in reversibly dysfunctional myocardium (p less than 0.003). Regional utilization of glucose normalized to regional perfusion in dysfunctional but viable myocardium was greater than that in normal myocardium (p less than 0.01). However, in both reversibly and persistently dysfunctional myocardium, utilization of glucose normalized to relative perfusion was markedly variable., Conclusions: The results indicate that preservation of oxidative metabolism is a necessary condition for recovery of function after coronary recanalization in patients with chronic coronary artery disease. Consequently, approaches that measure myocardial oxygen consumption, such as dynamic positron emission tomography with 11C-acetate, should facilitate the identification of those patients most likely to benefit from coronary revascularization.
- Published
- 1992
- Full Text
- View/download PDF
49. Binding of 5-(2'-[18F]fluoroethyl)flumazenil to central benzodiazepine receptors measured in living baboon by positron emission tomography.
- Author
-
Moerlein SM and Perlmutter JS
- Subjects
- Animals, Flumazenil metabolism, Male, Papio, Brain Chemistry, Flumazenil analogs & derivatives, Fluorine Radioisotopes, Receptors, GABA-A analysis, Tomography, Emission-Computed
- Abstract
5-(2'-[18F]Fluoroethyl)flumazenil ([18F]FEF), a fluorine-18-labeled analogue of the benzodiazepine antagonist flumazenil, was evaluated for use with positron emission tomography (PET). PET imaging of a baboon after i.v. injection of [18F]FEF showed that the radiofluorinated ligand rapidly localized in vivo within benzodiazepine receptor-rich cerebral tissues, and that selective disposition was retained for over 2 h. Coinjection of unlabeled flumazenil (0.55 mg/kg i.v.) abolished the heterogeneous cerebral distribution of the tracer; receptor-specific uptake was reduced by approximately 95%. The fluorinated benzodiazepine antagonist was degraded in vivo only to polar radiometabolites that do not cross the blood-brain barrier. [18F]FEF has advantages over existing PET radiopharmaceuticals, and is a promising radioligand for non-invasive evaluation of central benzodiazepine receptor binding in vivo.
- Published
- 1992
- Full Text
- View/download PDF
50. Production of fluorine-18 labeled (3-N-methyl)benperidol for PET investigation of cerebral dopaminergic receptor binding.
- Author
-
Moerlein SM, Banks WR, and Parkinson D
- Subjects
- Animals, Benperidol chemical synthesis, Benperidol metabolism, Female, In Vitro Techniques, Isotope Labeling, Macaca nemestrina, Male, Receptors, Dopamine D2, Benperidol analogs & derivatives, Brain diagnostic imaging, Fluorine Radioisotopes, Receptors, Dopamine metabolism, Tomography, Emission-Computed
- Abstract
The multi-millicurie synthesis of the D-2 receptor ligand [18F](3-N-methyl)benperidol (NMB; 1-[3-(4'- [18F]fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1- benzimidazolinyl)piperidine) is described. [18F]NMB was produced via a 3-step reaction sequence with an overall radiochemical yield of 5-10% and a specific activity greater than 3000 Ci/mmol within 100 min. In vitro binding assays indicated that NMB has high affinity for D-2 receptors in primate brain (K1 = 3.6 nM), with a receptor specificity exceeding that of spiperone. The technique described here permits the routine production of 10-20 mCi of this promising radiopharmaceutical for PET study of D-2 receptor binding in vivo.
- Published
- 1992
- Full Text
- View/download PDF
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