RESUMEN
BACKGROUND: The apolipoprotein E-deficient (apoE-/-) mouse is a well-established model for studying atherosclerosis. However, its small size limits its use in longitudinal positron emission tomography (PET) imaging studies. Recently, the apoE-/- rat has emerged as an alternative. With this study, we investigate the feasibility of using apoE-/- rats as an in vivo model for longitudinal atherosclerotic PET/CT imaging. RESULTS: ApoE-/- rats showed significantly higher [18F]FDG uptake than controls in the aortic arch (+ 18.5%, p < 0.001) and abdominal aorta (+ 31.0%, p < 0.001) at weeks 12, 26, and 51. ApoE-/- rats exhibited hypercholesterolemia, as evidenced by plasma cholesterol levels that were up to tenfold higher, and total hepatic cholesterol levels that were up to threefold higher than the control rats at the end of the study. Fast protein liquid chromatography cholesterol profiling indicated very high levels of pro-atherogenic apoB-containing very low-density lipoprotein and low-density lipoprotein fractions in the apoE-/- rats. Atherosclerotic lesions cover 19.9% of the surface of the aortic arch (p = 0.0013), and there was a significantly higher subendothelial accumulation of ED1-positive macrophages in the abdominal aorta of the apoE-/- rats compared to control rats (Ctrl) (p = 0.01). No differences in neutral sterols were observed but higher levels of bile acids were found in the apoE-/- rats. CONCLUSION: These data demonstrate early signs of hypercholesterolemia, high levels of bile acids, the development of atherosclerotic lesions, and macrophage accumulation in apoE-/- rats. Therefore, this model shows promise for atherosclerosis imaging studies.
RESUMEN
Fluorine-18-fluorodeoxyglucose ([18F]FDG) positron emission tomography (18F-FDG-PET) is widely used for the detection of inflammatory and infectious diseases. Although this modality has proven to be a useful diagnostic tool, reliable distinction of bacterial infection from sterile inflammation or even from a malignancy remains challenging. Therefore, there is a need for bacteria-specific tracers for PET imaging that facilitate a reliable distinction of bacterial infection from other pathology. The present study was aimed at exploring the potential of 2-[18F]-fluorodeoxysorbitol ([18F]FDS) as a tracer for detection of Enterobacterales infections. Sorbitol is a sugar alcohol that is commonly metabolized by bacteria of the Enterobacterales order, but not by mammalian cells, which makes it an attractive candidate for targeted bacterial imaging. The latter is important in view of the serious clinical implications of infections caused by Enterobacterales. Here we demonstrate that sorbitol-based PET can be applied to detect a broad range of clinical bacterial isolates not only in vitro, but also in blood and ascites samples from patients suffering from Enterobacterales infections. Notably, the possible application of [18F]FDS is not limited to Enterobacterales since Pseudomonas aeruginosa and Corynebacterium jeikeium also showed substantial uptake of this tracer. We conclude that [18F]FDS is a promising tracer for PET-imaging of infections caused by a group of bacteria that can cause serious invasive disease.
Asunto(s)
Infecciones Bacterianas , Fluorodesoxiglucosa F18 , Animales , Humanos , Tomografía de Emisión de Positrones/métodos , Sorbitol , Bacterias , MamíferosRESUMEN
Adenosine A2A and dopamine D2 receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A2A receptor-mediated modulation of D2 receptor binding in vivo using positron emission tomography (PET) with the D2 antagonist tracer [11C]raclopride. Healthy male Wistar rats (n = 8) were scanned (60 min dynamic scan) with [11C]raclopride at baseline and 7 days later following an acute administration of the A2A agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BPND) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [11C]raclopride BPND (p = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BPND from the k3/k4 ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [11C]raclopride scans after pretreatment with a vehicle (n = 5), a single dose of CGS21680 (1 mg/kg, n = 5), or a single dose of the A2A antagonist KW6002 (1 mg/kg, n = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group (p = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal k3/k4 ratio (p < 0.01), but k3 and k4 estimates may be less reliable. The BPND (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 (p = 0.080) or 1.961 ± 0.11 (p = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A2A agonist CGS21680, but not the antagonist KW6002, may reduce the D2 receptor availability in the striatum.
Asunto(s)
Dopamina , Receptor de Adenosina A2A , Adenosina/metabolismo , Agonistas del Receptor de Adenosina A2 , Antagonistas del Receptor de Adenosina A2 , Animales , Radioisótopos de Carbono , Cuerpo Estriado/metabolismo , Ligandos , Masculino , Tomografía de Emisión de Positrones/métodos , Racloprida , Ratas , Ratas Wistar , Receptor de Adenosina A2A/metabolismo , Receptores Dopaminérgicos/metabolismo , Roedores/metabolismoRESUMEN
Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D2/D3 agonist/H3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods: Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D2/D3 receptor ligand [11C]raclopride or the histamine H3 receptor ligand [11C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [11C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [11C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution (VT) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results: Dopamine D2/3 receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the VT values of [11C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H3 receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions: Target engagement of AG-0029 as an agonist at dopamine D2/D3 receptors and an antagonist at histamine H3 receptors could be demonstrated in the rat brain with [11C]raclopride and [11C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D2/D3 and moderate (submicromolar) affinity to H3 receptors.
Asunto(s)
Dopamina , Receptores de Dopamina D3 , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Histamina/metabolismo , Ligandos , Masculino , Mamíferos/metabolismo , Preparaciones Farmacéuticas/metabolismo , Tomografía de Emisión de Positrones/métodos , Racloprida , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismoRESUMEN
The histamine H3 receptor has been considered as a target for the treatment of various central nervous system diseases. Positron emission tomography (PET) studies with the radiolabeled potent and selective histamine H3 receptor antagonist [11C]GSK-189254 in rodents could be used to examine the mechanisms of action of novel therapeutic drugs or to assess changes of regional H3 receptor density in animal models of neurodegenerative disease. [11C]GSK-189254 was intravenously administered to healthy Wistar rats (n = 10), and a 60 min dynamic PET scan was carried out. Arterial blood samples were obtained during the scan to generate a metabolite-corrected plasma input function. PET data were analyzed using a one-tissue compartment model (1T2k), irreversible (2T3k) or reversible two-tissue compartment models (2T4k), graphical analysis (Logan and Patlak), reference tissue models (SRTM and SRTM2), and standard uptake values (SUVs). The Akaike information criterion and the standard error of the estimated parameters were used to select the most optimal quantification method. This study demonstrated that the 2T4k model with a fixed blood volume fraction and Logan graphical analysis can best describe the kinetics of [11C]GSK-189254 in the rat brain. SUV40-60 and the reference tissue-based measurements DVR(2T4k), BPND(SRTM), and SUV ratio could also be used as a simplified method to estimate H3 receptor availability in case blood sampling is not feasible.
Asunto(s)
Enfermedades Neurodegenerativas , Animales , Benzazepinas , Encéfalo/diagnóstico por imagen , Proteínas Portadoras , Histamina , Niacinamida/análogos & derivados , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Ratas , Ratas WistarRESUMEN
Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [18F]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [18F]Atorvastatin was synthesized via a previously optimized 18F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats (n = 7 for both groups), and for subsequent ex vivo biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [18F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [18F]atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [18F]atorvastatin kinetics in the liver. A strong correlation (R2 > 0.93) between quantitative Ki (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of Ki for monitoring [18F]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [18F]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [18F]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.
Asunto(s)
Atorvastatina/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Tomografía de Emisión de Positrones/métodos , Radiofármacos/análisis , Animales , Atorvastatina/administración & dosificación , Atorvastatina/análisis , Atorvastatina/química , Femenino , Radioisótopos de Flúor/administración & dosificación , Radioisótopos de Flúor/análisis , Eliminación Hepatobiliar , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/análisis , Masculino , Imagen Molecular/métodos , Radiofármacos/administración & dosificación , Ratas , Ratas Wistar , Factores Sexuales , Distribución TisularRESUMEN
BACKGROUND: High protein (HP) diets have been proposed to reduce body weight in humans. The diets are known to alter energy metabolism, which can affect the quality of [18F]FDG PET heart images. In this preclinical study, we therefore explore the impact of a prolonged HP diet on myocardial [18F]FDG uptake. METHODS: C57BL/6J (Black six (Bl6)) and apolipoprotein E-deficient (apoE-/-) mice were fed chow, a HP diet, or a low protein (LP) diet for 12 weeks. At baseline and after treatment, the animals were injected with 33.0 MBq of [18F]FDG and a 30 min PET/CT scan was made. Myocardial volume and [18F]FDG uptake were quantified using PET and the % of body fat was calculated from CT. RESULTS: Myocardial [18F]FDG uptake was similar for all diets at the follow-up scan but an increase between baseline and follow-up scans was noticed in the LP groups. Myocardial volume was significantly smaller in the C57BL HP group compared to the other Bl6 groups. Body weight increased less in the two HP groups compared to the chow and LP groups. Body fat percentage was significantly higher in the LP groups. This effect was stronger in C57BL mice (28.7%) compared to apoE-/- mice (15.1%). CONCLUSIONS: Myocardial uptake of [18F]FDG in mice is not affected by increased protein intake but [18F]FDG uptake increases when the amount of protein is lowered. A lower body weight and percentage of body fat were noticed when applying a HP diet.
Asunto(s)
Dieta Rica en Proteínas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Animales , Glucemia , Composición Corporal , Peso Corporal , Fluorodesoxiglucosa F18 , Corazón/diagnóstico por imagen , Ratones , Miocardio/metabolismo , Tamaño de los ÓrganosRESUMEN
Arginase hydrolyzes L-arginine and influences levels of polyamines and nitric oxide. Arginase overexpression is associated with inflammation and tumorigenesis. Thus, radiolabeled arginase inhibitors may be suitable PET tracers for staging arginase-related pathophysiologies. We report the synthesis and evaluation of 2 radiolabeled arginase inhibitors, 18F-FMARS and 18F-FBMARS, developed from α-substituted-2-amino-6-boronohexanoic acid derivatives. Methods: Arylboronic ester-derived precursors were radiolabeled via copper-mediated fluorodeboronation. Binding assays using arginase-expressing PC3 and LNCaP cells were performed. Autoradiography of lung sections from a guinea pig model of asthma overexpressing arginase and dynamic small-animal PET imaging with PC3-xenografted mice evaluated the radiotracers' specific binding and pharmacokinetics. Results:18F-fluorinated compounds were obtained with radiochemical yields of up to 5% (decay-corrected) and an average molar activity of 53 GBqâ µmol-1 Cell and lung section experiments indicated specific binding that was blocked up to 75% after pretreatment with arginase inhibitors. Small-animal PET studies indicated fast clearance of the radiotracers (7.3 ± 0.6 min), arginase-mediated uptake, and a selective tumor accumulation (SUV, 3.0 ± 0.7). Conclusion: The new 18F-fluorinated arginase inhibitors have the potential to map increased arginase expression related to inflammatory and tumorigenic processes. 18F-FBMARS showed the highest arginase-mediated uptake in PET imaging and a significant difference between uptake in control and arginase-inhibited PC3 xenografted mice. These results encourage further research to examine the suitability of 18F-FBMARS for selecting patients for treatments with arginase inhibitors.
Asunto(s)
Tomografía de Emisión de Positrones , Animales , Radioisótopos de Flúor , CobayasRESUMEN
Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3-dipolar compounds, its azide-alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)-catalyzed azide-alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate-specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation and in vitro studies, all the way to pre-clinical in vivo evaluation of fluorine-18- labeled PSMA-targeting 'F-PSMA-MIC' radiotracers (t1/2 =109.7â min). Pre-clinical data indicate that the modular PSMA-scaffold has similar binding affinity and imaging properties to the clinically used [68 Ga]PSMA-11. Furthermore, we demonstrated that targeting the arene-binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA-binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents.
Asunto(s)
Alquinos/química , Azidas/química , Reacción de Cicloadición , Radioisótopos de Flúor/química , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Trazadores Radiactivos , Humanos , MasculinoRESUMEN
The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D2 receptor antagonists were used to assess changes in [18F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (Ki) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [18F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p > 0.07, Cohen's d 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [18F]-FEOBV was significantly higher after haloperidol treatment (adjusted p = 0.022, Cohen's d = 2.51) than in controls. Compared to controls, the AUC of [18F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted p = 0.4, Cohen's d = 1.77) and raclopride (adjusted p = 0.052, Cohen's d = 1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment nonsignificantly increased Ki in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen's d = 1.1) while it reduced Ki in the cerebellum by 28% (adjusted p = 0.0004, Cohen's d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in Ki in the striatum (10%, adjusted p = 1, Cohen's d = 0.44) and a 40-50% lower Ki than controls in all other brain regions (adjusted p < 0.0005, Cohen's d = 3.3-4.7). The changes in Ki induced by the selective D2 receptor antagonist raclopride can in part be quantified using [18F]-FEOBV PET imaging. Haloperidol, a nonselective D2/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [18F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [18F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.
Asunto(s)
Antagonistas de los Receptores de Dopamina D2/farmacología , Radioisótopos de Flúor/sangre , Haloperidol/farmacología , Piperidinas/sangre , Racloprida/farmacología , Radiofármacos/sangre , Proteínas de Transporte Vesicular de Acetilcolina/metabolismo , Animales , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Radioisótopos de Flúor/administración & dosificación , Cinética , Masculino , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Piperidinas/administración & dosificación , Tomografía de Emisión de Positrones/métodos , Unión Proteica/efectos de los fármacos , Radiofármacos/administración & dosificación , Ratas , Ratas Wistar , Receptores sigma/antagonistas & inhibidores , Receptores sigma/metabolismoRESUMEN
PURPOSE: [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) is a radioligand for the vesicular acetylcholine transporter (VAChT), a marker of the cholinergic system. We evaluated the quantification of [18F]FEOBV in rats in control conditions and after partial saturation of VAChT using plasma and reference tissue input models and test-retest reliability. PROCEDURE: Ninety-minute dynamic [18F]FEOBV PET scans with arterial blood sampling were performed in control rats and rats pretreated with 10 µg/kg FEOBV. Kinetic analyses were performed using one- (1TCM) and two-tissue compartmental models (2TCM), Logan and Patlak graphical analyses with metabolite-corrected plasma input, reference tissue Patlak with cerebellum as reference tissue, standard uptake value (SUV) and SUV ratio (SUVR) using 60- or 90-min acquisition. To assess test-retest reliability, two dynamic [18F]FEOBV scans were performed 1 week apart. RESULTS: The 1TCM did not fit the data. Time-activity curves were more reliably estimated by the irreversible than the reversible 2TCM for 60 and 90 min as the influx rate Ki showed a lower coefficient of variation (COV, 14-24 %) than the volume of distribution VT (16-108 %). Patlak graphical analysis showed a good fit to the data for both acquisition times with a COV (12-27 %) comparable to the irreversible 2TCM. For 60 min, Logan analysis performed comparably to both irreversible models (COV 14-32 %) but showed lower sensitivity to VAChT saturation. Partial saturation of VAChT did not affect model selection when using plasma input. However, poor correlations were found between irreversible 2TCM and SUV and SUVR in partially saturated VAChT states. Test-retest reliability and intraclass correlation for SUV were good. CONCLUSION: [18F]FEOBV is best modeled using the irreversible 2TCM or Patlak graphical analysis. SUV should only be used if blood sampling is not possible.
Asunto(s)
Encéfalo/metabolismo , Modelos Biológicos , Piperidinas/farmacocinética , Radiofármacos/farmacocinética , Animales , Encéfalo/diagnóstico por imagen , Radioisótopos de Flúor , Humanos , Cinética , Ligandos , Masculino , Piperidinas/sangre , Tomografía de Emisión de Positrones , Radiofármacos/sangre , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Especificidad de la Especie , Distribución Tisular , Proteínas de Transporte Vesicular de Acetilcolina/metabolismoRESUMEN
In longitudinal PET studies, animals are repeatedly anesthetized which may affect the repeatability of PET measurements. The aim of this study was to assess the effect of anesthesia on the P-gp function as well as the reproducibility of [18F]MC225 PET scans. Thus, dynamic PET scans with blood sampling were conducted in 13 Wistar rats. Seven animals were exposed to isoflurane anesthesia 1 week before the PET scan ("Anesthesia-exposed" PET). A second group of six animals was used to evaluate the reproducibility of measurements of P-gp function at the blood-brain barrier (BBB) with [18F]MC225. In this group, two PET scans were made with a 1 week interval ("Test" and "Retest" PET). Pharmacokinetic parameters were calculated using compartmental models and metabolite-corrected plasma as an input function. "Anesthesia-exposed" animals showed a 28% decrease in whole-brain volume of distribution (VT) (p < 0.001) compared to "Test", where the animals were not previously anesthetized. The VT at "Retest" also decreased (19%) compared to "Test" (p < 0.001). The k2 values in whole-brain were significantly increased by 18% in "Anesthesia-exposed" (p = 0.005) and by 15% in "Retest" (p = 0.008) compared to "Test". However, no significant differences were found in the influx rate constant K1, which is considered as the best parameter to measure the P-gp function. Moreover, Western Blot analysis did not find significant differences in the P-gp expression of animals not pre-exposed to anesthesia ("Test") or pre-exposed animals ("Retest"). To conclude, anesthesia may affect the brain distribution of [18F]MC225 but it does not affect the P-gp expression or function.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cintigrafía , Radiofármacos/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Masculino , Ratas Wistar , Reproducibilidad de los Resultados , Roedores/metabolismoRESUMEN
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
RESUMEN
PURPOSE: An important issue in rodent imaging is the question whether a mixed population of male and female animals can be used rather than animals of a single sex. For this reason, the present study examined the test-retest stability of positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in male rats and female rats at different phases of the estrous cycle. PROCEDURES: Long-Evans rats (age 1 year) were divided into three groups: (1) males (n = 6), (2) females in metestrous (low estrogen levels, n = 9), and (3) females in proestrous (high estrogen levels, n = 7). Two standard [18F]FDG scans with rapid arterial blood sampling were made at an interval of 10 days in subjects anesthetized with isoflurane and oxygen. Body temperature, heart rate, and blood oxygenation were continuously monitored. Regional cerebral metabolic rates of glucose were calculated using a Patlak plot with plasma radioactivity as input function. RESULTS: Regional metabolic rate of glucose (rCMRglucose) in male and female rats, or [18F]FDG uptake in females at proestrous and metestrous, was not significantly different, but females showed significantly higher standardized uptake values (SUVs) and Patlak flux than males, particularly in the initial scan. The relative difference between the scans and the test-retest variability (TRV) were greater in females than in males. Intra-class correlation coefficients (ICCs) of rCMRglucose, SUV, normalized SUV, and glucose flux were good to excellent in males but poor to moderate in females. CONCLUSIONS: Based on these data for [18F]FDG, the mixing of sexes in imaging studies of the rodent brain will result in an impaired test-retest stability of PET data and a need for larger group sizes to maintain statistical power in group comparisons. The observed differences between males and females do not indicate any specific gender difference in cerebral metabolism but are related to different levels of non-radioactive glucose in blood plasma during isoflurane anesthesia.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Fluorodesoxiglucosa F18/química , Tomografía de Emisión de Positrones , Animales , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Masculino , Análisis de Flujos Metabólicos , Ratas Long-Evans , Factores de TiempoRESUMEN
Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (18F-FDG) can be applied to detect infection and inflammation. However, it was so far not known to what extent bacterial pathogens may contribute to the PET signal. Therefore, we investigated whether clinical isolates of frequently encountered bacterial pathogens take up 18F-FDG in vitro, and whether FDG inhibits bacterial growth as previously shown for 2-deoxy-glucose. 22 isolates of Gram-positive and Gram-negative bacterial pathogens implicated in fever and inflammation were incubated with 18F-FDG and uptake of 18F-FDG was assessed by gamma-counting and µPET imaging. Possible growth inhibition by FDG was assayed with Staphylococcus aureus and the Gram-positive model bacterium Bacillus subtilis. The results show that all tested isolates accumulated 18F-FDG actively. Further, 18F-FDG uptake was hampered in B. subtilis pts mutants impaired in glucose uptake. FDG inhibited growth of S. aureus and B. subtilis only to minor extents, and this effect was abrogated by pts mutations in B. subtilis. These observations imply that bacteria may contribute to the signals observed in FDG-PET infection imaging in vivo. Active bacterial FDG uptake is corroborated by the fact that the B. subtilis phosphotransferase system is needed for 18F-FDG uptake, while pts mutations protect against growth inhibition by FDG.
Asunto(s)
Bacillus subtilis/crecimiento & desarrollo , Fluorodesoxiglucosa F18/farmacocinética , Staphylococcus aureus/crecimiento & desarrollo , Bacillus subtilis/efectos de los fármacos , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Fiebre/diagnóstico por imagen , Fiebre/microbiología , Fluorodesoxiglucosa F18/farmacología , Glucosa/metabolismo , Humanos , Inflamación/diagnóstico por imagen , Inflamación/microbiología , Mutación , Fosfotransferasas/genética , Fosfotransferasas/metabolismo , Tomografía de Emisión de Positrones/métodos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
The estrogen receptor (ER) is a target for endocrine therapy in breast cancer patients. Individual quantification of ERα and ERß expression, rather than total ER levels, might enable better prediction of the response to treatment. We recently developed the tracer 2-18F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol (18F-FHNP) for assessment of ERß levels with PET. In the current study, we investigated several pharmacokinetic analysis methods to quantify changes in ERß availability with 18F-FHNP PET. Methods: Male nude rats were subcutaneously inoculated in the shoulder with ERα/ERß-expressing SKOV3 human ovarian cancer cells. Two weeks after tumor inoculation, a dynamic 18F-FHNP PET scan with arterial blood sampling was acquired from rats treated with vehicle or various concentrations of estradiol (nonspecific ER agonist) or genistein (ERß-selective agonist). Different pharmacokinetic models were applied to quantify ERß availability in the tumor. Results: Irreversible-uptake compartmental models fitted the kinetics of 18F-FHNP uptake better than reversible models. The irreversible 3-tissue-compartment model, which included both the parent and the metabolite input function, gave results comparable to those of the irreversible 2-tissue-compartment model with only a parent input function, indicating that radioactive metabolites contributed little to the tumor uptake. Patlak graphical analysis gave metabolic rates (Ki, the irreversible uptake rate constant) comparable to compartment modeling. The Ki values correlated well with ERß expression but not with ERα, confirming that Ki is a suitable parameter to quantify ERß expression. SUVs at 60 min after tracer injection also correlated (r2 = 0.47; P = 0.04) with ERß expression. A reduction in 18F-FHNP tumor uptake and Ki values was observed in the presence of estradiol or genistein. Conclusion:18F-FHNP PET enables assessment of ERß availability in tumor-bearing rats. The most suitable parameter to quantify ERß expression is the Ki However, a simplified static imaging protocol for determining the SUVs can be applied to assess ERß levels.
Asunto(s)
Receptor beta de Estrógeno/biosíntesis , Naftoles/farmacocinética , Tomografía de Emisión de Positrones/métodos , Piridinas/farmacocinética , Radiofármacos/farmacocinética , Animales , Línea Celular Tumoral , Estradiol/farmacocinética , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/genética , Femenino , Genisteína/farmacocinética , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Modelos Estadísticos , Neoplasias Ováricas/diagnóstico por imagen , Ratas , Ratas Desnudas , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: Small animal positron emission tomography (PET) can be used to detect small changes in neuroreceptor availability. This often requires rapid arterial blood sampling. However, current catheterization procedures do not allow repeated blood sampling. We have developed a procedure which allows arterial sampling on repeated occasions in the same animal. PROCEDURES: Eleven male Wistar rats were two times catheterized via a superficial branch of a femoral artery and scanned with [(11)C]MPDX and blood sampling. PET images were co-registered to a magnetic resonance imaging (MRI) template. Regional tracer distribution volumes (V T) in the brain were calculated by the Logan analysis. The procedure was repeated after 1 week. RESULTS: Surgery was successful in 90 % of the cases, and discomfort was minor. The V T data showed small differences between test and retest, low between subject variability, and a strong agreement between and within subjects. CONCLUSION: Repeated quantitative imaging with a high reproducibility is possible with this approach.
Asunto(s)
Recolección de Muestras de Sangre/métodos , Tomografía de Emisión de Positrones/métodos , Xantinas/química , Animales , Peso Corporal , Ligandos , Masculino , Ratas Wistar , Receptor de Adenosina A1/metabolismo , Reproducibilidad de los ResultadosRESUMEN
(11)C-PBR28 is a second-generation translocator protein (TSPO) tracer with characteristics supposedly superior to the most commonly used tracer for neuroinflammation, (R)-(11)C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of (11)C-PBR28 in rodent models of neuroinflammation have been published yet. Therefore, this study aimed to evaluate (11)C-PBR28 as a tool for detection and quantification of neuroinflammation in preclinical research and to compare its imaging properties with (R)-(11)C-PK11195. The herpes simplex encephalitis (HSE) model was used for induction of neuroinflammation in male Wistar rats. Six or 7 d after virus inoculation, a dynamic (11)C-PBR28 or (R)-(11)C-PK11195 PET scan with arterial blood sampling was obtained. Pharmacokinetic modeling was performed on the PET data and analyzed using volumes of interest and a voxel-based approach. Volume-of-interest- and voxel-based analysis of (11)C-PBR28 images showed overexpression of TSPO in brain regions known to be affected in the HSE rat model. (11)C-PBR28 was metabolized faster than (R)-(11)C-PK11195, with a metabolic half-life in plasma of 5 and 21 min, respectively. Overall, (11)C-PBR28 was more sensitive than (R)-(11)C-PK11195 in detecting neuroinflammation. The binding potential (BPND) of (11)C-PBR28 was significantly higher (P < 0.05) in the medulla (176%), pons (146%), midbrain (101%), hippocampus (85%), thalamus (73%), cerebellum (54%), and hypothalamus (49%) in HSE rats than in control rats, whereas (R)-(11)C-PK11195 showed a higher BPND only in the medulla (32%). The BPND in control animals was not significantly different between tracers, suggesting that the nonspecific binding of both tracers is similar. (11)C-PBR28 was more sensitive than (R)-(11)C-PK11195 in the detection of TSPO overexpression in the HSE rat model, because more brain regions with significantly increased tracer uptake could be found, irrespective of the data analysis method used. These results suggest that (11)C-PBR28 should be able to detect more subtle changes in microglial activation in preclinical models of neuroinflammation.
Asunto(s)
Encefalitis por Herpes Simple/metabolismo , Isoquinolinas/farmacocinética , Pirimidinas/farmacocinética , Animales , Transporte Biológico , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Isoquinolinas/metabolismo , Cinética , Masculino , Tomografía de Emisión de Positrones , Pirimidinas/metabolismo , Ratas , Ratas WistarRESUMEN
PURPOSE: Sigma-1 receptor ligands modulate the release of several neurotransmitters and intracellular calcium signaling. We examined the binding of a radiolabeled sigma-1 agonist in the aging rat brain with positron emission tomography (PET). PROCEDURES: Time-dependent uptake of [(11)C]SA4503 was measured in the brain of young (1.5 to 3 months) and aged (18 to 32 months) Wistar Hannover rats, and tracer-kinetic models were fitted to this data, using metabolite-corrected plasma radioactivity as input function. RESULTS: In aged animals, the injected probe was less rapidly metabolized and cleared. Logan graphical analysis and a 2-tissue compartment model (2-TCM) fit indicated changes of total distribution volume (V T) and binding potential (BP ND) of the tracer. BP ND was reduced particularly in the (hypo)thalamus, pons, and medulla. CONCLUSIONS: Some areas showed reductions of ligand binding with aging whereas binding in other areas (cortex) was not significantly affected.