RESUMEN
OBJECTIVE: Recent studies have suggested that epidermal burn injuries are associated with inflammation and immune dysfunction. Simvastatin has been shown to possess potent anti-inflammatory properties. Thus, we hypothesized that simvastatin protects against burn-induced apoptosis in the spleen via its anti-inflammatory activity. METHODS: Wild-type, tumor necrosis factor alpha knockout (TNF-α KO) and NF-κB KO mice were subjected to full-thickness burn injury or sham treatment. The mice then were treated with or without simvastatin, and the spleen was harvested to measure the extent of apoptosis. Expression levels of TNF-α and NF-κB were also determined in spleen tissue and serum. RESULTS: Burn injury induced significant splenic apoptosis and systemic cytokine production. Simvastatin protected the spleen from apoptosis, reduced cytokine production in the serum, and increased the survival rate. Simvastatin decreased burn-induced TNF-α and NF-κB expression in the spleen and serum. TNF-α and NF-κB KO mice demonstrated lower levels of apoptosis in spleen in response to burn injury. Simvastatin did not further decrease burn-caused apoptosis and mortality in either strain of KO mice. CONCLUSIONS: Simvastatin reduces burn-induced splenic apoptosis via downregulation of the TNF-α/NF-κB pathway.
Asunto(s)
Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Quemaduras/tratamiento farmacológico , FN-kappa B/metabolismo , Simvastatina/farmacología , Bazo/patología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Quemaduras/metabolismo , Quemaduras/patología , Citocinas/sangre , Regulación hacia Abajo , Ratones Noqueados , FN-kappa B/sangre , Simvastatina/uso terapéutico , Factor de Necrosis Tumoral alfa/sangreRESUMEN
In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15-60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg-1, i.p.), whole brain radioactivity uptake was diminished by 25%-40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacocinética , Hidrocarburos Yodados/química , Marcaje Isotópico/métodos , Isradipino/farmacocinética , Neuroimagen/métodos , Radiofármacos/farmacocinética , Animales , Encéfalo/metabolismo , Encéfalo/ultraestructura , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/metabolismo , Canales de Calcio/metabolismo , Radioisótopos de Carbono , Dimetilformamida/química , Evaluación Preclínica de Medicamentos , Semivida , Isradipino/química , Isradipino/metabolismo , Masculino , Permeabilidad , Tomografía de Emisión de Positrones , Compuestos de Amonio Cuaternario/química , Radiofármacos/química , Radiofármacos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Mitochondrial dysfunction has been closely related to many pathologic processes, such as cellular apoptosis. Alterations in organelle membrane potential are associated with mitochondrial dysfunction. A fluorine-18 labeled phosphonium compound: (18)F-triphenylphosphonium ((18)F-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis. METHODS: Studies were conducted in both ex vivo cell lines and in vivo using a burned animal model. Uptake of (18)F-TPP was assessed in PC-3 cells by gamma counting under the following conditions: graded levels of extracellular potassium concentrations, incubation with carbonyl cyanide m-chlorophenylhydrazone and staurosporine. Apoptosis was studied in a burn animal model using terminal deoxynucleotidyl transferase dUTP nick end labeling staining and simultaneous assessment of (18)F-TPP uptake by biodistribution. RESULTS: We found that stepwise membrane depolarization by potassium (K) resulted in a linear decrease in (18)F-TPP uptake, with a slope of 0.62 ± 0.08 and a correlation coefficient of 0.936 ± 0.11. Gradually increased concentrations of m-chlorophenylhydrazone lead to decreased uptake of (18)F-TPP. Staurosporine significantly decreased the uptake of (18)F-TPP in PC-3 cells from 14.2 ± 3.8% to 5.6 ± 1.3% (P < 0.001). Burn-induced significant apoptosis (sham: 4.4 ± 1.8% versus burn: 24.6 ± 6.7 %; P < 0.005) and a reduced uptake of tracer in the spleens of burn-injured animals as compared with sham burn controls (burn: 1.13 ± 0.24% versus sham: 3.28 ± 0.67%; P < 0.005). Biodistribution studies demonstrated that burn-induced significant reduction in (18)F-TPP uptake in spleen, heart, lung, and liver, which were associated with significantly increased apoptosis. CONCLUSIONS: (18)F-TPP is a promising new voltage sensor for detecting mitochondrial dysfunction and apoptosis in various tissues.
Asunto(s)
Apoptosis , Quemaduras/diagnóstico por imagen , Radioisótopos de Flúor , Potencial de la Membrana Mitocondrial , Compuestos Organofosforados/uso terapéutico , Animales , Carbonil Cianuro m-Clorofenil Hidrazona , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones , Potasio , Bazo/diagnóstico por imagen , Estaurosporina , ValinomicinaRESUMEN
Hypermetabolism is a prominent feature of burn injury, and altered mitochondria function is presumed to contribute to this state. Recently, brown adipose tissue (BAT) was found to be present not only in rodents but also in humans, and its activity is associated with resting metabolic rate. In this report, we elucidate the relationship between burn injury-induced hypermetabolism and BAT activity and the possible role of the mitochondria-targeted peptide SS31 in attenuating burn injury-induced hypermetabolism by using a rat burn injury model. We demonstrate that burn injury induces morphological changes in interscapular BAT (iBAT). Burn injury was associated with iBAT activation, and this effect was positively correlated with increased energy expenditure. BAT activation was associated with augmentation of mitochondria biogenesis, and UCP1 expression in the isolated iBAT mitochondria. In addition, the mitochondria-targeted peptide SS31 attenuated burn injury-induced hypermetabolism, which was accompanied by suppression of UCP1 expression in isolated mitochondria. Our results suggest that BAT plays an important role in burn injury-induced hypermetabolism through its morphological changes and expression of UCP1.
Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Quemaduras/tratamiento farmacológico , Depuradores de Radicales Libres/uso terapéutico , Canales Iónicos/metabolismo , Mitocondrias/efectos de los fármacos , Enfermedades Mitocondriales/prevención & control , Proteínas Mitocondriales/metabolismo , Oligopéptidos/uso terapéutico , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/ultraestructura , Animales , Quemaduras/metabolismo , Quemaduras/patología , Quemaduras/fisiopatología , Regulación hacia Abajo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Canales Iónicos/antagonistas & inhibidores , Masculino , Microscopía Electrónica de Transmisión , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Enfermedades Mitocondriales/etiología , Proteínas Mitocondriales/antagonistas & inhibidores , Recambio Mitocondrial/efectos de los fármacos , Terapia Molecular Dirigida , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Escápula , Organismos Libres de Patógenos Específicos , Proteína Desacopladora 1 , Regulación hacia Arriba/efectos de los fármacosRESUMEN
This study was to obtain voxel-wise PET accuracy and precision using tissue-segmentation for attenuation correction. We applied multiple thresholds to the CTs of 23 patients to classify tissues. For six of the 23 patients, MR images were also acquired. The MR fat/in-phase ratio images were used for fat segmentation. Segmented tissue classes were used to create attenuation maps, which were used for attenuation correction in PET reconstruction. PET bias images were then computed using the PET reconstructed with the original CT as the reference. We registered the CTs for all the patients and transformed the corresponding bias images accordingly. We then obtained the mean and standard deviation bias atlas using all the registered bias images. Our CT-based study shows that four-class segmentation (air, lungs, fat, other tissues), which is available on most PET-MR scanners, yields 15.1%, 4.1%, 6.6%, and 12.9% RMSE bias in lungs, fat, non-fat soft-tissues, and bones, respectively. An accurate fat identification is achievable using fat/in-phase MR images. Furthermore, we have found that three-class segmentation (air, lungs, other tissues) yields less than 5% standard deviation of bias within the heart, liver, and kidneys. This implies that three-class segmentation can be sufficient to achieve small variation of bias for imaging these three organs. Finally, we have found that inter- and intra-patient lung density variations contribute almost equally to the overall standard deviation of bias within the lungs.
RESUMEN
The serotonergic system is implicated in disordered emotional behavior. Autism is characterized by impaired processing of emotional information. The serotonergic (5-HT) system is also critically involved in brain development, and abnormal brain synthesis of serotonin is observed in autism. Furthermore, whole blood and platelet serotonin have been reported to be elevated in autism. The authors examined the CNS serotonin system in autism in vivo. 5-HT2 receptors were visualized by PET imaging of [18F]setoperone-binding in this pilot study of 6 high-functioning autistic adults and 10 matched-control participants. Autism subjects had less thalamic [18F]setoperone binding than controls, when covaried for age, but no difference reached significance in other areas. A negative relationship between thalamic binding and history of language impairment was also observed. Further studies will be needed to gain a clearer picture of the role of the 5-HT system in autism.
Asunto(s)
Trastorno Autístico/metabolismo , Radioisótopos de Flúor , Neuroimagen Funcional/psicología , Pirimidinonas , Receptores de Serotonina 5-HT2/metabolismo , Tálamo/metabolismo , Adulto , Trastorno Autístico/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios de Casos y Controles , Femenino , Neuroimagen Funcional/métodos , Humanos , Trastornos del Lenguaje/complicaciones , Trastornos del Lenguaje/diagnóstico por imagen , Trastornos del Lenguaje/metabolismo , Masculino , Proyectos Piloto , Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/psicología , Ensayo de Unión Radioligante/métodos , Ensayo de Unión Radioligante/psicología , Radiofármacos , Tálamo/diagnóstico por imagenRESUMEN
With the growing number of biotechnology products and drug delivery systems entering preclinical and clinical studies, pharmacological imaging studies with PET play an increasingly significant role. Such studies often require investigation of slow and complex pharmacokinetics (PK). This suggests labeling of the drug candidate with radionuclides that have long physical half-lives. Among the currently available PET positron emitters, ¹²4I has the longest physical half-life (4.2 days). This, combined with the well-investigated behavior of iodine in vivo, makes ¹²4I very attractive for pharmacological studies. However, the high energy of the positrons emitted by ¹²4I and the presence of single photons in the ¹²4I emission can potentially introduce limitations in the quantitative analysis of the images. The objective of this research was to determine whether the use of ¹²4I as a PET label provides data quality suitable for PK studies. The study was carried out using MicroPET P4 scanner (Siemens/Concorde Microsystems). Spatial resolution, count-rate performance, sensitivity and scatter fraction were measured using a line source and a cylindrical phantom. Model animal studies in rats and cynomolgus monkeys were carried out using human recombinant proteins. The proteins were labeled with ¹²4I, up to 185 MBq/mg. The transaxial and axial spatial resolutions in the center of the camera were satisfactory and higher for OSEM3D/MAP than FORE-2DFBP (FWHM 2.52 vs 3.31 mm, and 3.10 vs 3.69 mm). Linearity of the true coincidence count-rate was observed up to 44 MBq. Animal studies demonstrated excellent delineation and resolution of even very small organs. At optimal doses, 2-10 MBq per animal for rodents and 4-10 MBq per kg of body weight for larger animals, the quality of numerical data was appropriate for PK analysis in all experimental timeframes from minutes (dynamic studies) to 10 days. Overall, the data suggest that ¹²4I is an excellent label for quantitative pharmacological PET imaging studies.
Asunto(s)
Radioisótopos de Yodo/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Animales , Haplorrinos , Humanos , Radioisótopos de Yodo/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Functional neuroimaging studies suggest that a lateral network in the brain is associated with the sensory aspects of pain perception while a medial network is associated with affective aspects. The highest concentration of opioid receptors is in the medial network. There is significant evidence that endogenous opioids are central to the experience of pain and analgesia. We applied an integrative multimodal imaging approach during acupuncture. We found functional magnetic resonance imaging signal changes in the orbitofrontal cortex, insula, and pons and [11C]diprenorphine positron emission tomography signal changes in the orbitofrontal cortex, medial prefrontal cortex, insula, thalamus, and anterior cingulate cortex. These findings include brain regions within both the lateral and medial pain networks.
Asunto(s)
Analgesia por Acupuntura/métodos , Diprenorfina , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Analgesia/métodos , Radioisótopos de Carbono , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Diprenorfina/farmacocinética , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/metabolismo , Dimensión del Dolor/métodos , Puente/diagnóstico por imagen , Puente/metabolismo , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/metabolismo , Radiografía , Tálamo/diagnóstico por imagen , Tálamo/metabolismoRESUMEN
BACKGROUND: The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent studies of genetics, treatment, and imaging have highlighted the role of DAT in attention-deficit/hyperactivity disorder (ADHD). The findings of in vivo neuroimaging of DAT in ADHD have been somewhat discrepant, however. METHOD: Dopamine transporter binding was measured using a highly selective ligand (C-11 altropane) and positron emission tomography (PET). The sample consisted of 47 well-characterized, treatment-naïve, nonsmoking, non-comorbid adults with and without ADHD. Additionally, control subjects had few symptoms of ADHD. RESULTS: Results showed significantly increased DAT binding in the right caudate in adults with ADHD compared with matched control subjects without this disorder. CONCLUSIONS: These results confirm abnormal DAT binding in the striatum of adults with ADHD and provide further support that dysregulation of DAT may be an important component of the pathophysiology of ADHD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Cocaína/análogos & derivados , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Tomografía de Emisión de Positrones , Adolescente , Adulto , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Trastorno por Déficit de Atención con Hiperactividad/patología , Distribución de Chi-Cuadrado , Cuerpo Estriado/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The feasibility of off-line positron emission tomography/computed tomography (PET/CT) for routine three dimensional in-vivo treatment verification of proton radiation therapy is currently under investigation at Massachusetts General Hospital in Boston. In preparation for clinical trials, phantom experiments were carried out to investigate the sensitivity and accuracy of the method depending on irradiation and imaging parameters. Furthermore, they addressed the feasibility of PET/CT as a robust verification tool in the presence of metallic implants. These produce x-ray CT artifacts and fluence perturbations which may compromise the accuracy of treatment planning algorithms. Spread-out Bragg peak proton fields were delivered to different phantoms consisting of polymethylmethacrylate (PMMA), PMMA stacked with lung and bone equivalent materials, and PMMA with titanium rods to mimic implants in patients. PET data were acquired in list mode starting within 20 min after irradiation at a commercial luthetium-oxyorthosilicate (LSO)-based PET/CT scanner. The amount and spatial distribution of the measured activity could be well reproduced by calculations based on the GEANT4 and FLUKA Monte Carlo codes. This phantom study supports the potential of millimeter accuracy for range monitoring and lateral field position verification even after low therapeutic dose exposures of 2 Gy, despite the delay between irradiation and imaging. It also indicates the value of PET for treatment verification in the presence of metallic implants, demonstrating a higher sensitivity to fluence perturbations in comparison to a commercial analytical treatment planning system. Finally, it addresses the suitability of LSO-based PET detectors for hadron therapy monitoring. This unconventional application of PET involves countrates which are orders of magnitude lower than in diagnostic tracer imaging, i.e., the signal of interest is comparable to the noise originating from the intrinsic radioactivity of the detector itself. In addition to PET alone, PET/CT imaging provides accurate information on the position of the imaged object and may assess possible anatomical changes during fractionated radiotherapy in clinical applications.
Asunto(s)
Interpretación de Imagen Asistida por Computador/métodos , Tomografía de Emisión de Positrones/métodos , Prótesis e Implantes , Terapia de Protones , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Conformacional/métodos , Tomografía Computarizada por Rayos X/métodos , Algoritmos , Artefactos , Metales , Método de Montecarlo , Fantasmas de Imagen , Plásticos , Tomografía de Emisión de Positrones/instrumentación , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Técnica de Sustracción , Tomografía Computarizada por Rayos X/instrumentaciónRESUMEN
OBJECTIVE: The abuse potential of methylphenidate has been related to the drug's capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-a-day osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediate-release methylphenidate. METHOD: Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (C(max)) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmotic-release methylphenidate). Plasma d-methylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. RESULTS: Despite similar C(max) values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate. CONCLUSIONS: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Metilfenidato/farmacocinética , Tomografía de Emisión de Positrones , Administración Oral , Adolescente , Adulto , Conducta Adictiva/etiología , Encéfalo/efectos de los fármacos , Cocaína/análogos & derivados , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Preparaciones de Acción Retardada , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Metilfenidato/efectos adversos , Metilfenidato/sangre , Persona de Mediana Edad , Ósmosis , Detección de Abuso de SustanciasRESUMEN
Many inflammatory responses are mediated by activation of the transcription factor, nuclear factor-kappa B (NF-κB), and a wide variety of human diseases involve abnormal regulation of its expression. In this investigation, we evaluated the effect of smoke inhalation injury on NF-κB expression in lung using two strains of NF-κB reporter mice. Groups of reporter mice with viral thymidine kinase (TK) or "fire fly" luciferase (Luc) genes under control by the NF-κB promoter (TK/NF-κB mice and Luc/NF-κB mice) were subjected to nonlethal smoke inhalation injury. Sham-treated animals served as controls. Twenty-four hours (each animal was injected intravenously with either 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine (FHBG) (~ 1.0 mCi) or luciferin (1.0 mg). One hour later, the TK/NF-κB mice were studied by micro-positron emission tomography (µ-PET) imaging using a Concord P4 µ-PET camera, and the Luc/NF-κB mice were studied by bioluminescence imaging with a charge-coupled device camera. The µ-PET data demonstrated that smoke injury produced massive increases in NF-κB expression (FHBG-standardized uptake value: 3.1 vs 0.0) 24 hours after smoke inhalation, which was reduced 48 hours after smoke inhalation, but still significantly different than the control. Qualitative analysis of the bioluminescence data revealed a remarkably similar effect of burn NF-κB luciferase expression in vivo. Biodistribution studies of FHBG uptake and luciferase activity in lung tissue demonstrated a similar increase 24 hours after injury, which was reduced 48 hours later, but still significantly higher than the sham. The present data with these models providing longitudinal imaging data on the same mouse may prove useful in the examination of the factors producing lung injury by smoke inhalation, as well as the treatment(s) for the damage produced with and without burn injury.
Asunto(s)
Quemaduras por Inhalación/patología , Pulmón/patología , Imagen Molecular , Humo/efectos adversos , Factor de Transcripción ReIA/metabolismo , Animales , Quemaduras por Inhalación/metabolismo , Pulmón/metabolismo , Masculino , Ratones , Ratones Transgénicos , Tomografía de Emisión de Positrones , Distribución TisularRESUMEN
There is converging evidence of the role of catecholamine dysregulation in the underlying pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent genetic, treatment, and imaging studies have highlighted the role of DAT in ADHD. There is an emerging literature on in vivo neuroreceptor imaging of DAT in ADHD and control subjects reported by a number of groups internationally. A comprehensive review of existing imaging studies of DAT binding in ADHD shows that six of eight independent studies by six different groups have reported increased DAT binding in (mostly) treatment-naïve children and adults with ADHD. Although there is fair agreement regarding the presence and direction of abnormal DAT binding, there remains disagreement as to the magnitude of the finding and the importance of many potentially confounding variables, including clinical characteristics and imaging methodology. Three studies by three different groups have reported decreased DAT binding after methylphenidate treatment. Interpretation of the latter finding awaits clarification of the issue of timing of drug administration and imaging to disentangle receptor occupancy from downregulation.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Cocaína/análogos & derivados , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Células Receptoras Sensoriales/diagnóstico por imagen , Tomografía Computarizada de Emisión/métodos , Factores de Edad , Animales , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Mapeo Encefálico , Isótopos de Carbono/farmacocinética , Cocaína/farmacocinética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Humanos , Células Receptoras Sensoriales/metabolismo , Factores de TiempoRESUMEN
UNLABELLED: This study describes the radiosynthesis and preliminary biologic evaluation of trans-9(RS)-(18)F-fluoro-3,4(RS,RS)-methyleneheptadecanoic acid ((18)F-FCPHA) as a new potential probe for assessing myocardial fatty acid metabolism by PET. This fatty acid, containing a cyclopropyl moiety in the beta,gamma-position, was designed to enter the myocardium by the same mechanism as natural fatty acids and to undergo partial metabolism before being trapped in the cell. METHODS: (18)F-FCPHA and the beta-methyl analog 8(RS)-(18)F-fluoro-3(RS)-methylheptadecanoic acid ((18)F-FBMHA) were prepared from their corresponding mesylate precursors by nucleophilic substitution. The precursors used for labeling were fully characterized, and the data were consistent with the proposed structures. Biodistribution studies of each tracer were performed with Sprague-Dawley rats at 5 and 60 min after injection. Sequential imaging of a rhesus monkey injected with 222 MBq of (18)F-FCPHA was performed by use of a microPET camera. RESULTS: At 5 and 60 min, heart uptake values measured as mean +/- SD percentage injected dose per gram (%ID/g) in rats for (18)F-FCPHA were 1.55 +/- 0.72 and 1.43 +/- 0.14, respectively. The heart-to-blood ratios at 5 and 60 min, an indication of target definition, were 25.8 and 20.4, respectively. The heart-to-lung ratios at 5 and 60 min were 3.3 and 4.6, respectively. Bone accumulation (%ID/g), an indication of defluorination, was 0.16 +/- 0.03 at 5 min and increased to 0.70 +/- 0.39 at 60 min. The heart-to-blood ratio obtained with (18)F-FBMHA was 2.6 at 5 min and did not change significantly at 60 min. Imaging of the monkey heart after injection of (18)F-FCPHA showed an initial spike of activity corresponding to blood flow followed by a plateau at 10 min. CONCLUSION: The cyclopropyl moiety in (18)F-FCPHA does have a significant influence on heart accumulation, as suggested by the high heart-to-blood ratio and the fast blood clearance in rats. These results, along with the remarkable quality of the PET images, indicate the potential of this new class of labeled fatty acids for use in studying heart disease by PET.
Asunto(s)
Ácidos Grasos/metabolismo , Ácidos Grasos/farmacocinética , Corazón/diagnóstico por imagen , Miocardio/metabolismo , Tomografía de Emisión de Positrones/métodos , Animales , Evaluación Preclínica de Medicamentos , Macaca mulatta , Masculino , Tasa de Depuración Metabólica , Especificidad de Órganos , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
UNLABELLED: (18)F-FDG and (18)F-FDG-labeled white blood cells ((18)F-FDG-WBCs) are valuable radiopharmaceuticals for imaging focal sites of inflammation and infection. In the present study, the imaging properties of both radiotracers were compared in sterile and septic inflammation models. METHODS: Groups of adult male Sprague-Dawley rats (100-120 g) were injected in the left posterior thigh muscle with saline solution (group 1: controls, n = 15), 0.100 mL of turpentine oil (group 2: sterile inflammation, n = 26), 10(9) viable Escherichia coli bacteria (group 3: E. coli septic inflammation, n = 29), or 10(8) viable Pseudomonas aeruginosa bacteria (group 4: P. aeruginosa septic inflammation, n = 25). Twenty-four hours later, the animals were divided into 2 groups: One received (18)F-FDG intravenously and the other received human white blood cells (WBCs) labeled in vitro with (18)F-FDG injected intravenously. Biodistribution and microPET studies were performed 1 h after radiotracer injection. One hour after injection with cell-associated or free (18)F-FDG, phosphorimaging of abscess and contralateral muscle was performed in specimens collected from animals in groups 1, 2, and 3. The region of interest was selected within the abscess wall and values were converted to kBq/g using a (14)C calibration standard curve. Thin-layer radiochromatography (TLRC) was performed to study the chemical forms of (18)F within the WBCs. RESULTS: Whole-body biodistribution demonstrated a significantly higher uptake ratio of (18)F-FDG-WBCs compared with (18)F-FDG in all sterile and septic inflammation models (t test: sterile, P = 0.048; E. coli, P = 0.040; P. aeruginosa, P = 0.037). microPET imaging confirmed the greater performance of (18)F-FDG-WBCs versus (18)F-FDG in the sterile inflammation model and in both E. coli and P. aeruginosa septic models. Phosphorimaging analysis showed higher (18)F-FDG-WBC uptake than (18)F-FDG in the sterile inflammation and P. aeruginosa septic models and similar tissue uptake in the E. coli septic model. Time course labeling and TLRC of lysed WBCs demonstrated that (18)F-FDG was retained as (18)F-FDG-6-phosphate inside WBCs for at least 2 h, corresponding to the time frame of analysis. CONCLUSION: (18)F-FDG-WBCs gave better results compared with (18)F-FDG in all sterile and septic inflammation models. These data suggest that (18)F-FDG-WBC PET may be a useful technique for tracking focal inflammatory lesions in the body.
Asunto(s)
Infecciones por Escherichia coli/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Inflamación/diagnóstico por imagen , Leucocitos/diagnóstico por imagen , Infecciones por Pseudomonas/diagnóstico por imagen , Animales , Infecciones por Escherichia coli/metabolismo , Fluorodesoxiglucosa F18/farmacocinética , Inflamación/metabolismo , Masculino , Tasa de Depuración Metabólica , Infecciones por Pseudomonas/metabolismo , Cintigrafía , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución TisularRESUMEN
PURPOSE: Fatty acid amide hydrolase (FAAH), a catabolic enzyme which regulates lipid transmitters in the endocannabinoid system, is an avidly sought therapeutic and positron emission tomography (PET) imaging target for studies involving addiction and neurological disorders. We report the synthesis of a new fluorine-18-labeled FAAH inhibitor, trans-3-(4, 5-dihydrooxazol-2-yl)phenyl-4-[(18)F]fluorocyclohexylcarbamate ([(18)F]FCHC), and its evaluation in rat brain. PROCEDURES: The synthesis of [(18)F]FCHC was conducted via a 3-step, 1-pot reaction, resulting in uncorrected radiochemical yields between 10 and 20% (n = 5) relative to [(18)F]fluoride, with specific activities of >5 Ci/µmol at the end of the synthesis. The radiosynthesis was seamlessly automated using a commercial radiofluorination apparatus. Ex vivo biodistribution and preliminary PET imaging studies were carried out in male Sprague-Dawley rats. RESULTS: Rat brain biodistribution at 2 min post-injection showed a standard uptake value of 4.6 ± 0.1 in the cortex, which increased to 7.8 ± 0.1 at 40 min. Pretreatment with the selective FAAH inhibitor URB597 reduced uptake of radioactivity in all brain regions by >90%, with 98 % blockade in the FAAH-rich cortex. PET imaging was consistent with biodistribution studies. CONCLUSIONS: [(18)F]FCHC appears to be a highly sensitive (18)F-labeled radiotracer for imaging FAAH in the central nervous system, and these results warrant further imaging in nonhuman primates.
Asunto(s)
Amidohidrolasas/metabolismo , Carbamatos/síntesis química , Neuroimagen/métodos , Oxazoles/síntesis química , Animales , Encéfalo/diagnóstico por imagen , Carbamatos/química , Carbamatos/farmacocinética , Radioisótopos de Flúor/farmacocinética , Masculino , Oxazoles/química , Oxazoles/farmacocinética , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Tomografía Computarizada por Rayos XRESUMEN
The dopamine transporter (DAT), located presynaptically on dopamine neurons, provides a marker for Parkinson's disease (Pd) and attention deficit hyperactivity disorder (ADHD). In ADHD, DAT density levels are elevated, while in Pd these levels are depleted. The depletion of DAT levels also corresponds with the loss of dopamine. We now describe the design, synthesis, biology, and SPECT imaging in nonhuman primates of second-generation (99m)technetium-based tropane ligands that bind potently and selectively to the DAT. We demonstrate that improved selectivity and biological stability allows sufficient agent to enter the brain and label the DAT in vivo to provide a quantitative measure of DAT density in nonhuman primates. We introduce FLUORATEC (N-[(2-((3'-N'-propyl-(1"R)-3"alpha-(4-fluorophenyl)tropane-2"beta-1-propanoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]technetium(V) oxide), a DAT imaging agent that has emerged from these studies and is now in phase 1 clinical trials in the U.S.
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana/metabolismo , Proteínas del Tejido Nervioso , Compuestos de Organotecnecio/síntesis química , Radiofármacos/síntesis química , Tropanos/síntesis química , Animales , Encéfalo/diagnóstico por imagen , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Técnicas In Vitro , Ligandos , Macaca fascicularis , Masculino , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/farmacocinética , Unión Proteica , Radiofármacos/química , Radiofármacos/farmacocinética , Estereoisomerismo , Tomografía Computarizada de Emisión de Fotón Único , Tropanos/química , Tropanos/farmacocinéticaRESUMEN
Without exception, therapeutic and addictive drugs that produce their primary effects by blocking monoamine transporters in brain contain an amine nitrogen in their structure. This fundamental canon of drug design was based on a prevailing premise that an amine nitrogen is required to mimic the structures of monoamine neurotransmitters and other natural products. Non-amines, a novel class of compounds that contain no amine nitrogen, block monoamine transporters in the nM range and display markedly high selectivity for monoamine transporters, but not for receptors. Non-amines retain the spectrum of biochemical and pharmacological properties characteristic of amine-bearing counterparts. These novel drugs compel a revision of current concepts of drug-monoamine transporter complex formation and open avenues for discovery of a new generation of therapeutic drugs.
Asunto(s)
Inhibidores de Captación de Dopamina/metabolismo , Glicoproteínas de Membrana , Moduladores del Transporte de Membrana , Proteínas de Transporte de Membrana/antagonistas & inhibidores , Proteínas de Transporte de Membrana/metabolismo , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Animales , Aminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Macaca mulatta , Masculino , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Saimiri , Relación Estructura-ActividadRESUMEN
It is expected that both noise and activity distribution can have impact on the detectability of a myocardial defect in a cardiac PET study. In this work, we performed phantom studies to investigate the detectability of a defect in the myocardium for different noise levels and activity distributions. We evaluated the performance of three reconstruction schemes: Filtered Back-Projection (FBP), Ordinary Poisson Ordered Subset Expectation Maximization (OP-OSEM), and Point Spread Function corrected OSEM (PSF-OSEM). We used the Channelized Hotelling Observer (CHO) for the task of myocardial defect detection. We found that the detectability of a myocardial defect is almost entirely dependent on the noise level and the contrast between the defect and its surroundings.
Asunto(s)
Miocardio/patología , Tomografía de Emisión de Positrones/instrumentación , Algoritmos , Diseño de Equipo , Femenino , Humanos , Masculino , Fantasmas de ImagenRESUMEN
Exercise is a component of the clinical management for burn patients, to help reduce muscle wasting associated with prolonged hospitalization. In the present study the authors examined 2-deoxy-2-[18F] fluoro-D-glucose (18FDG) uptake in mice subjected to burn injury with and without exercise. Mice had their the dorsums shaven, were placed in molds, and the exposed area was immersed in 90°C water for 9 seconds followed by resuscitation with saline (2 ml) to produce a 30% full-thickness burn injury. Twenty-four hours later, the mice were subjected to treadmill exercise for 1 hour. Before exercise, mice were injected with ~50 µCi 18FDG. Mice were killed after running and a complete biodistribution was performed. Exercise produced a stimulation of 18FDG update by skeletal muscle and heart, while reducing 18FDG accumulation in brain. Burn injury had no significant effect on 18FDG update by skeletal muscle, but did increase 18FDG accumulation in heart, while reducing 18FDG accumulation in brain. However, exercise combined with a burn injury produced a significant increase in 18FDG uptake in the skeletal muscle compared with the burned mice, as great as that produced in the sham animals subjected to exercise. The combination of burn plus exercise appeared to prevent the stimulation of 18FDG uptake by the heart produced by burn injury alone. Exercise treatment did not correct the changes in 18FDG uptake in the brain produced by burn injury. Separately, exercise and burn injury significantly increased serum interleukin-6 levels, increases that were higher when exercise was combined with the burn injury. These findings suggest that exercise may exert some therapeutic effects in burn patients by tissue-specific modulation of glucose metabolism, and these changes may be related to interleukin-6.