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1.
Mol Psychiatry ; 22(12): 1759-1766, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28242869

RESUMEN

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.


Asunto(s)
Alcoholismo/metabolismo , Encéfalo/metabolismo , Inflamación/metabolismo , Microglía/metabolismo , Receptores de GABA/metabolismo , Acetamidas , Adulto , Alcoholismo/diagnóstico por imagen , Alcoholismo/genética , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Radioisótopos de Carbono , Células Cultivadas , Citocinas/metabolismo , Femenino , Humanos , Inflamación/diagnóstico por imagen , Inflamación/genética , Lipopolisacáridos , Masculino , Monocitos/inmunología , Neuroimagen , Polimorfismo de Nucleótido Simple , Tomografía de Emisión de Positrones , Piridinas , Radiofármacos , Receptores de GABA/genética , Índice de Severidad de la Enfermedad
2.
Neuroimage ; 141: 71-80, 2016 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-27426839

RESUMEN

The positron emission tomography (PET) radioligand (-)-[(18)F]flubatine is specific to α4ß2(⁎) nicotinic acetylcholine receptors (nAChRs) and has promise for future investigation of the acetylcholine system in neuropathologies such as Alzheimer's disease, schizophrenia, and substance use disorders. The two goals of this work were to develop a simplified method for α4ß2(⁎) nAChR quantification with bolus plus constant infusion (B/I) (-)-[(18)F]flubatine administration, and to assess the radioligand's sensitivity to acetylcholine fluctuations in humans. Healthy human subjects were imaged following either bolus injection (n=8) or B/I (n=4) administration of (-)-[(18)F]flubatine. The metabolite-corrected input function in arterial blood was measured. Free-fraction corrected distribution volumes (VT/fP) were estimated with modeling and graphical analysis techniques. Next, sensitivity to acetylcholine was assessed in two ways: 1. A bolus injection paradigm with two scans (n=6), baseline (scan 1) and physostigmine challenge (scan 2; 1.5mg over 60min beginning 5min prior to radiotracer injection); 2. A single scan B/I paradigm (n=7) lasting up to 240min with 1.5mg physostigmine administered over 60min beginning at 125min of radiotracer infusion. Changes in VT/fP were measured. Baseline VT/fP values were 33.8±3.3mL/cm(3) in thalamus, 12.9±1.6mL/cm(3) in cerebellum, and ranged from 9.8 to 12.5mL/cm(3) in other gray matter regions. The B/I paradigm with equilibrium analysis at 120min yielded comparable VT/fP values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means <4% different). Changes in VT/fP following physostigmine administration were small and most pronounced in cortical regions, ranging from 0.8 to 4.6% in the two-scan paradigm and 2.8 to 6.5% with the B/I paradigm. These results demonstrate the use of B/I administration for accurate quantification of (-)-[(18)F]flubatine VT/fP in 120min, and suggest possible sensitivity of (-)-[(18)F]flubatine binding to physostigmine-induced changes in acetylcholine levels.


Asunto(s)
Acetilcolina/metabolismo , Benzamidas/farmacocinética , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Imagen Molecular/métodos , Tomografía de Emisión de Positrones/métodos , Receptores Nicotínicos/metabolismo , Adulto , Benzamidas/administración & dosificación , Encéfalo/diagnóstico por imagen , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Simulación por Computador , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Infusiones Intraventriculares , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Neurológicos , Neurotransmisores/metabolismo , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución Tisular , Adulto Joven
3.
Synapse ; 65(12): 1309-18, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21674627

RESUMEN

OBJECTIVE: [F-18]Nifene is a PET radioligand developed to image α4ß2* nicotinic acetylcholine receptors (nAChR) in the brain. This work assesses the in vivo binding and imaging characteristics of [F-18]nifene in rhesus monkeys for the development of PET experiments examining nAChR binding. METHODS: Dynamic PET imaging experiments with [F-18]nifene were acquired in four anesthetized Macaca mulatta (rhesus) monkeys using a microPET P4 scanner. Data acquisition was initiated with a bolus injection of 109 ± 17 MBq [F-18]nifene and the time course of the radioligand in the brain was measured for up to 120 min. For two experiments, a displacement dose of (-)nicotine (0.03 mg kg(-1) , i.v.) was given 45-60 min post injection and followed 30 min later with a second [F-18]nifene injection to measure radioligand nondisplaceable uptake. Time activity curves were extracted in the regions of the antereoventral thalamus (AVT), lateral geniculate nucleus region (LGN), frontal cortex, and the cerebellum (CB). RESULTS: The highest levels of [F-18]nifene uptake were observed in the AVT and LGN. Target-to-CB ratios reached maximum values of 3.3 ± 0.4 in the AVT and 3.2 ± 0.3 in the LGN 30-45 min postinjection. Significant binding of [F-18]nifene was observed in the subiculum, insula cortex, temporal cortex, cingulate gyrus, frontal cortex, striatum, and midbrain areas. The (-)nicotine displaced bound [F-18]nifene to near background levels within 15 min postdrug injection. No discernable displacement was observed in the CB, suggesting its potential as a reference region. Logan graphical estimates using the CB as a reference region yielded binding potentials of 1.6 ± 0.2 in the AVT and 1.3 ± 0.1 in the LGN. The postnicotine injection displayed uniform nondisplaceable uptake of [F-18]nifene throughout gray and white brain matter. CONCLUSIONS: [F-18]Nifene exhibits rapid equilibration and a moderately high target to background binding profile in the α4ß2* nAChR rich regions of the brain, thus providing favorable imaging characteristics as a PET radiotracer for nAChR assay.


Asunto(s)
Piridinas/metabolismo , Pirroles/metabolismo , Receptores Nicotínicos/metabolismo , Animales , Sitios de Unión/fisiología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Femenino , Macaca mulatta , Masculino , Neuroimagen/métodos , Tomografía de Emisión de Positrones/métodos , Unión Proteica/fisiología
4.
Synapse ; 65(7): 592-600, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21484878

RESUMEN

UNLABELLED: [F-18]Mefway was developed to provide an F-18 labeled positron emission tomography (PET) neuroligand with high affinity for the serotonin 5-HT(1A) receptor to improve the in vivo assessment of the 5-HT(1A) system. The goal of this work was to compare the in vivo kinetics of [F-18]mefway, [F-18]MPPF, and [C-11]WAY100635 in the rhesus monkey. METHODS: Each of four monkeys were given bolus injections of [F-18]mefway, [C-11]WAY100635, and [F-18]MPPF and scans were acquired with a microPET P4 scanner. Arterial blood was sampled to assay parent compound throughout the time course of the PET experiment. Time activity curves were extracted in the high 5-HT(1A) binding areas of the anterior cingulate cortex (ACG), mesial temporal cortex, raphe nuclei, and insula cortex. Time activity curves were also extracted in the cerebellum, which was used as a reference region. The in vivo kinetics of the radiotracers were compared based on the nondisplaceable distribution volume (V(ND) ) and binding potential (BP(ND) ). RESULTS: At 30 min, the fraction of radioactivity in the plasma due to parent compound was 19%, 28%, and 29% and cleared from the arterial plasma at rates of 0.0031, 0.0078, and 0.0069 (min⁻¹) ([F-18]mefway, [F-18]MPPF, [C-11]WAY100635). The BP(ND) in the brain regions were mesial temporal cortex: 7.4 ± 0.6, 3.1 ± 0.4, 7.0 ± 1.2, ACG: 7.2 ± 1.2, 2.1 ± 0.2, 7.9 ± 1.2; raphe nuclei: 3.7 ± 0.6, 1.3 ± 0.3, 3.3 ± 0.7; and insula cortex: 4.2 ± 0.6, 1.2 ± 0.1, 4.7 ± 1.0 for [F-18]mefway, [F-18]MPPF, and [C-11]WAY100635 respectively. CONCLUSIONS: In the rhesus monkey, [F-18]mefway has similar in vivo kinetics to [C-11]WAY100635 and yields greater than 2-fold higher BP(ND) than [F-18]MPPF. These properties make [F-18]mefway a promising radiotracer for 5-HT(1A) assay, providing higher counting statistics and a greater dynamic range in BP(ND).


Asunto(s)
Encéfalo/diagnóstico por imagen , Piperazinas/farmacocinética , Piridinas/farmacocinética , Radiofármacos/farmacocinética , Animales , Radioisótopos de Carbono/farmacocinética , Radioisótopos de Flúor/farmacocinética , Macaca mulatta , Tomografía de Emisión de Positrones/métodos
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