RESUMEN
UNLABELLED: As mouse imaging has become more challenging in preclinical research, efforts have been made to develop dedicated PET systems. Although these systems are currently used for the study of physiopathologic murine models, they present some drawbacks for brain studies, including a low temporal resolution that limits the pharmacokinetic study of radiotracers. The aim of this study was to demonstrate the ability of a radiosensitive intracerebral probe to measure the binding of a radiotracer in the mouse brain in vivo. METHODS: The potential of a probe 0.25 mm in diameter for pharmacokinetic studies was assessed. First, Monte Carlo simulations followed by experimental studies were used to evaluate the detection volume and sensitivity of the probe and its adequacy for the size of loci in the mouse brain. Second, ex vivo autoradiography of 5-hydroxytryptamine receptor 1A (5-HT(1A)) receptors in the mouse brain was performed with the PET radiotracer 2'-methoxyphenyl-(N-2'-pyridinyl)-p-(18)F-fluorobenzamidoethylpiperazine ((18)F-MPPF). Finally, the binding kinetics of (18)F-MPPF were measured in vivo in both the hippocampus and the cerebellum of mice. RESULTS: Both the simulations and the experimental studies demonstrated the feasibility of using small probes to measure radioactive concentrations in specific regions of the mouse brain. Ex vivo autoradiography showed a heterogeneous distribution of (18)F-MPPF consistent with the known distribution of 5-HT(1A) in the mouse brain. Finally, the time-activity curves obtained in vivo were reproducible and validated the capacity of the new probe to accurately measure (18)F-MPPF kinetics in the mouse hippocampus. CONCLUSION: Our results demonstrate the ability of the tested radiosensitive intracerebral probe to monitor binding of PET radiotracers in anesthetized mice in vivo, with high temporal resolution suited for compartmental modeling.
Asunto(s)
Cerebelo/diagnóstico por imagen , Radioisótopos de Flúor , Hipocampo/diagnóstico por imagen , Piperazinas/farmacocinética , Piridinas/farmacocinética , Receptor de Serotonina 5-HT1A/metabolismo , Animales , Cerebelo/metabolismo , Simulación por Computador , Radioisótopos de Flúor/farmacocinética , Hipocampo/metabolismo , Masculino , Ratones , Método de Montecarlo , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinéticaRESUMEN
In vivo small animal imaging with multiple modalities has become an important tool in modern biomedical research. Indeed, combining exploratory techniques allows simultaneous recording of complementary data, which is required to elucidate complex physiopathological mechanisms. In this field, because of strict technical constraints in vivo, an exciting challenge remains in the combination of Nuclear Magnetic Resonance (NMR) and Positron Emission Tomography (PET). Coupling NMR with a radiosensitive Beta MicroProbe offers therefore a very interesting technical alternative. Here, we assessed the feasibility of this new combination by theoretically evaluating the ability of the Beta MicroProbe to monitor radioactivity in a magnet. To that aim, we modelled with Geant4 the effect of an intense magnetic field on the probe field of view and showed that the field should not have an impact on the global efficiency of the probe.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Imagen por Resonancia Magnética/métodos , Radioisótopos/análisis , Animales , Partículas beta , Encéfalo/patología , Radioisótopos de Carbono , Circulación Cerebrovascular/fisiología , Campos Electromagnéticos , Electrones , Metabolismo Energético/fisiología , Radioisótopos de Flúor , Microelectrodos/normas , Modelos Teóricos , Radioisótopos de Oxígeno , Tomografía de Emisión de Positrones/métodos , RadiactividadRESUMEN
UNLABELLED: The evaluation of every new radiotracer involves pharmacokinetic studies on small animals to determine its biodistribution and local kinetics. To extract relevant biochemical information, time-activity curves for the regions of interest are mathematically modeled on the basis of compartmental models that require knowledge of the time course of the tracer concentration in plasma. Such a time-activity curve, usually termed input function, is determined in small animals by repeated blood sampling and subsequent counting in a well counter. The aim of the present work was to propose an alternative to blood sampling in small animals, since this procedure is labor intensive, exposes the staff to radiation, and leads to an important loss of blood, which affects hematologic parameters. METHODS: Monte Carlo simulations were performed to evaluate the feasibility of measuring the arterial input function using a positron-sensitive microprobe placed in the femoral artery of a rat. The simulation results showed that a second probe inserted above the artery was necessary to allow proper subtraction of the background signal arising from tracer accumulation in surrounding tissues. This approach was then validated in vivo in 5 anesthetized rats. In a second set of experiments, on 3 rats, a third probe was used to simultaneously determine 18F-FDG accumulation in the striatum. RESULTS: The high temporal resolution of the technique allowed accurate determination of the input function peak after bolus injection of 18F-FDG. Quantitative input functions were obtained after normalization of the arterial time-activity curve for a late blood sample. In the second set of experiments, compartmental modeling was achieved using either the blood samples or the microprobe data as the input function, and similar kinetic constants were found in both cases. CONCLUSION: Although direct quantification proved difficult, the microprobe allowed accurate measurement of arterial input function with a high temporal resolution and no blood loss. The technique, because offering adequate sensitivity and temporal resolution for kinetic measurements of radiotracers in the blood compartment, should facilitate quantitative modeling for radiotracer studies in small animals.
Asunto(s)
Algoritmos , Arterias/metabolismo , Cuerpo Estriado/metabolismo , Fluorodesoxiglucosa F18/farmacocinética , Técnica de Dilución de Radioisótopos , Radiometría/métodos , Animales , Arterias/diagnóstico por imagen , Cuerpo Estriado/diagnóstico por imagen , Fluorodesoxiglucosa F18/sangre , Tasa de Depuración Metabólica , Modelos Biológicos , Radiometría/instrumentación , Cintigrafía , RatasRESUMEN
Understanding brain disorders, the neural processes implicated in cognitive functions and their alterations in neurodegenerative pathologies, or testing new therapies for these diseases would benefit greatly from combined use of an increasing number of rodent models and neuroimaging methods specifically adapted to the rodent brain. Besides magnetic resonance (MR) imaging and functional MR, positron-emission tomography (PET) remains a unique methodology to study in vivo brain processes. However, current high spatial-resolution tomographs suffer from several technical limitations such as high cost, low sensitivity, and the need of restraining the animal during image acquisition. We have developed a beta(+)-sensitive high temporal-resolution system that overcomes these problems and allows the in vivo quantification of cerebral biochemical processes in rodents. This beta-MICROPROBE is an in situ technique involving the insertion of a fine probe into brain tissue in a way very similar to that used for microdialysis and cell electrode recordings. In this respect, it provides information on molecular interactions and pathways, which is complementary to that produced by these technologies as well as other modalities such as MR or fluorescence imaging. This study describes two experiments that provide a proof of concept to substantiate the potential of this technique and demonstrate the feasibility of quantifying brain activation or metabolic depression in individual living rats with 2-[(18)F]fluoro-2-deoxy-d-glucose and standard compartmental modeling techniques. Furthermore, it was possible to identify correctly the origin of variations in glucose consumption at the hexokinase level, which demonstrate the strength of the method and its adequacy for in vivo quantitative metabolic studies in small animals.
Asunto(s)
Encéfalo/metabolismo , Neuronas/metabolismo , Animales , Corteza Cerebral/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Metabolismo Energético , Fluorodesoxiglucosa F18/administración & dosificación , Fluorodesoxiglucosa F18/farmacocinética , Masculino , Malonatos/administración & dosificación , Microdiálisis/instrumentación , Microdiálisis/métodos , Radiometría/instrumentación , Radiometría/métodos , Ratas , Ratas Sprague-Dawley , Corteza Somatosensorial/metabolismo , Succinato Deshidrogenasa/antagonistas & inhibidoresRESUMEN
UNLABELLED: Our aim was to show the ability of a recently developed beta(+)-range-sensitive intracerebral probe (SIC) to measure, in vivo, the binding of radioligands in small animals. METHODS: The potential of the device for pharmacokinetic studies was evaluated by measurement of the dynamic striatal binding of (11)C-raclopride, a well-documented D(2) dopaminergic receptor ligand, in rat brain after intravenous injection of the labeled compound. The effects of preinjection of the unlabeled ligand (raclopride, 2 mg/kg intravenously) and of increasing the synaptic dopamine level (amphetamine treatment, 1 mg/kg intravenously) or of depleting synaptic dopamine (reserpine pretreatment, 5 mg/kg intraperitoneally) on in vivo (11)C-raclopride binding were monitored by SIC. RESULTS: The radioactivity curves measured as a function of time were reproducible and consistent with previous studies using PET imaging (ratio of striatum to cerebellum, 2.6 +/- 0.3 after 20 min). Further studies showed significant displacement of (11)C-raclopride by its stable analog. Finally, the device proved its capacity to accurately detect changes in (11)C-raclopride binding after a sudden (amphetamine) or a gradual (reserpine) modulation of endogenous dopamine levels. CONCLUSION: These results show that the new device can monitor binding of PET ligands in anesthetized rodents in vivo, with high temporal resolution.