The aim of this study was to demonstrate the potential of a wireless pixelated β+-sensitive intracerebral probe (PIXSIC) for in vivo positron emission tomographic (PET) radiopharmacology in awake and ...freely moving rodents. The binding of 11Craclopride to D2 dopamine receptors was measured in anesthetized and awake rats following injection of the radiotracer. Competitive binding was assessed with a cold raclopride injection 20 minutes later. The device can accurately monitor binding of PET ligands in freely moving rodents with a high spatiotemporal resolution. Reproducible time-activity curves were obtained for pixels throughout the striatum and cerebellum. A significantly lower 11Craclopride tracer-specific binding was observed in awake animals. These first results pave the way for PET tracer pharmacokinetics measurements in freely moving rodents.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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 β+-sensitive high temporal-resolution system that overcomes these problems and allows the in vivo quantification of cerebral biochemical processes in rodents. This β-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 2-18Ffluoro-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.
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. 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. 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. 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.
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.
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.
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.
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.
Purpose
The aim of this work was to demonstrate the pharmacokinetic potential of a wireless pixelated β
+
-sensitive probe (PIXSIC).
Procedures
The binding of 2′-methoxyphenyl-(
N
-2′-pyridinyl)-p-
...18
Ffluoro-benzamidoethylpiperazine (
18
FMPPF), a 5-HT
1A
serotonin receptor radiopharmaceutical, was measured in anesthetized rats and compared to microPET data. The effects of a 5-HT
1A
antagonist injection on
in vivo
18
FMPPF binding were monitored by PIXSIC.
Results
PIXSIC allowed differentiating the radioactive kinetics according to the location of its pixels in the hippocampus, cortex, corpus callosum, and cerebellum. The device accurately detected the changes in
18
FMPPF binding, after 5-HT
1A
antagonist blockade. The time–activity curves were reproducible and consistent with kinetics obtained simultaneously with a microPET camera.
Conclusions
These results demonstrate the ability of the PIXSIC device to record reliably the binding of PET ligands, with a high spatiotemporal resolution in anesthetized rodents. These first
in vivo
results are a key stage on the path to its implementation in awake freely moving animals.
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.
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.
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.
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.
Preclinical behavior neuroimaging gathers simultaneous assessment of behavior and functional brain imaging. It is a potential key breakthrough to improve the understanding of brain processes and ...assess the validity of preclinical studies in drug development. Achieving such a combination is difficult, anesthesia or restraints inherent to conventional nuclear imaging preclude its use for behavior studies. In that context, we have proposed an original strategy using submillimetric probes to directly measures positrons inside the rat brain. This paper gives the results of Monte Carlo simulations of a new generation of intracerebral positron probe based on a complementary metal oxide semi-conductor monolithic active pixel sensor. We present the results obtained for a probe into a large homogeneous volume of radioactive water ( 18 F) leading to a sensitivity of 0.88 cps<inline-formula> <tex-math notation="LaTeX">{\cdot } </tex-math></inline-formula>Bq<inline-formula> <tex-math notation="LaTeX">^{ {-1}} {\cdot } </tex-math></inline-formula>mm 3 and a mean energy deposition by positrons of 15.1 keV. Simulation in simplified brain-shaped sources modeling a 11 C-raclopride experiment shows that the implanted volume modeling the left putamen contribute to 92.4% of the signal from positrons. We also investigate the effects of the thickness of the sensitive layer, the energy threshold and pixel dimensions on the detection capacities of the sensor. We demonstrate that an increase in the sensitive thickness from 18 to 190 <inline-formula> <tex-math notation="LaTeX"> \mu \text{m} </tex-math></inline-formula> would lead to an increase of positrons sensitivity by a factor of 1.74, but to a decrease of the direct (positrons) to indirect (<inline-formula> <tex-math notation="LaTeX"> \gamma </tex-math></inline-formula>-rays and electrons) sensitivity ratio by a factor of 1.59. Finally, we show that for a threshold lower than about 5 keV the effect of the pixel dimensions is negligible.
IMIC is a Monolithic Active Pixel Sensor prototype for the MAPSSIC project dedicated to direct detection of low energy β+ rays in the brain of awake and freely-moving rats using CMOS technology. ...Former experiments using a β+ Si probe developed within the PIXSIC project validated a methodological proof of concept. However, conducting routinely such measurements would require improvements with respect to the passive pixel sensors employed in PIXSIC. The new IMIC circuit is fabricated in a 180 nm CMOS Image Sensor Technology and features a matrix of 16 × 128 pixels, which are 30 × 50 μm 2 large. The sensor has a needle-like aspect ratio (610 μm × 12 000 μm). The chip is produced on a 18 μm high-resistivity epitaxial layer substrate. The foreseen application requires high sensitivity to β-rays while being immune to background γ-rays. Another severe constraint is the limited power dissipation in order to minimize the thermal impact on the brain. IMIC is a fully-programmable digital sensor. The pixel design is based on the front-end architecture of the ALPIDE chip. However modifications have been made to store the information inside fired pixels between two readouts allowing low data throughput. The circuit is controlled through the SPI protocol, which allows for setting all the necessary polarization signals. The results of post-layout simulations show a high signal to noise ratio (>40) and low power dissipation of 115 μW/matrix. Laboratory characterization using β-rays validate these predictions and demonstrated that the slow readout can cope with the expected low activity (≈ 120 hits/matrix/s).
The aim of this study was to demonstrate the potential of a wireless pixelated β+-sensitive intracerebral probe (PIXSIC) for in vivo positron emission tomographic (PET) radiopharmacology in awake and ...freely moving rodents. The binding of
Craclopride to D
dopamine receptors was measured in anesthetized and awake rats following injection of the radiotracer. Competitive binding was assessed with a cold raclopride injection 20 minutes later. The device can accurately monitor binding of PET ligands in freely moving rodents with a high spatiotemporal resolution. Reproducible time-activity curves were obtained for pixels throughout the striatum and cerebellum. A significantly lower
Craclopride tracer-specific binding was observed in awake animals. These first results pave the way for PET tracer pharmacokinetics measurements in freely moving rodents.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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