PIXSIC: A Wireless Intracerebral Radiosensitive Probe in Freely Moving Rats

International audienceThe 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 [ 11 C]raclopride to D 2 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 [ 11 C]raclopride tracer–specific binding was observed in awake animals. These first results pave the way for PET tracer pharmacokinetics measurements in freely moving rodents

BioALTO platform: An experimental platform at ALTO for hadron therapy research

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Arterial input function measurement without blood sampling using a β-microprobe in rats

International audienceThe evaluation of every new radiotracer involves pharmacoki-netic 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 18 F-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 18 F-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, com-partmental 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

Arterial input function measurement without blood sampling using a β-microprobe in rats

International audienceThe evaluation of every new radiotracer involves pharmacoki-netic 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 18 F-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 18 F-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, com-partmental 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

PIXSIC, a Pixelated β(+)-Sensitive Probe for Radiopharmacological Investigations in Rat Brain: Binding Studies with [(18)F]MPPF.

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Potential of the wireless radiosensitive intracerebral probe PIXSIC to monitor PET radiotracers in anaesthetized and awake rat

In neuroscience, functional imaging with positron emission tomography (PET) and behavioural assays in rodents are complementary approaches, despite the fact that they are rarely associated simultaneously because general anaesthesia inherent to PET precludes behavioural studies. To address this methodological limit, we have developped a radiosensitive pixelated intracerebral probe named PIXSIC that provides access to the combination of simultaneous observations of molecular and behavioural parameters on rodents. PIXSIC proposes a novel strategy for in vivo recording of the local time-activity curves of PET radiopharmaceuticals. It relies on a sub-millimetre pixelated probe of Si (200 µm thick, 690 µm wide and 17 mm long hosting 10 pixels with dimension 200 µm x 500 µm) implanted into the brain region of interest by stereotaxic surgery. Positrons resulting from decays of a PET radiotracer are detected by reverse-biased, high-resistivity silicon diodes. The system aims at time-resolved high sensitivity measurements in a volume of a few mm3 defined similarly as for the Beta-Microprobe by the positron range within tissues. The pixelated detection scheme adds "imaging" features as it allows recording of the time-activity curves in different brain regions along the probe position. PIXSIC has a compact and autonomous design based on a radiofrequency data exchange link that allows for full freedom in the animals motion and behavioural activity while limiting stress during acquisition. The first biological validations were performed on anaesthetized rats implanted with two probes, one in the region of interest (hippocampus or striatum, according to the radiotracer) and the other one in a control region (cerebellum). We used [11C]-raclopride for dopamine D2 receptors and [18F]-MPPF for serotonin 5HT1A receptors. According to our previous studies with the Beta-Microprobe (J Nucl Med 2002, 43(2):227-33; Eur J Nucl Med 2002 29(9) 1237-47), the radioactive signals measured with the PIXSIC pixels are reproducible and well-correlated with the distributions of the targeted receptors. The simultaneous measurement of implanted rats in a small animal PET camera confirmed the similarity between PIXSIC and microPET time-activity curves. Moreover, the binding curves highlighted the possibility for PIXSIC to distinguish different tracer kinetics within the structure of interest (cortex/striatum or cortex/hippocampus) in accordance to the stereotaxic location of the pixels. In addition, PIXSIC allowed us to perform the first kinetic measurements of [11C]-raclopride and [18F]-MPPF on awake and freely moving rats. In conclusion, PIXSIC constitutes an unprecedented instrumental methodology for connecting PET molecular imaging and behavioral measurements with freely-moving rodents

Rat interleukin-1 beta binding sites in rat hypothalamus and pituitary gland.

International audienceIn this study, radiolabeled recombinant rat interleukin-1 beta (r125I-IL-1 beta) was used to localize and characterize IL-1 beta binding in rat hypothalamus and pituitary gland by quantitative autoradiography. The ability of this ligand to bind to type I IL-1 receptor was first tested on murine lymphoma cells (EL-4). In the rat-tissue sections, high densities of specific r125I-IL-1 beta binding sites were localized in the anterior as well as the posterior pituitary and in the choroid plexus. A fine labeling was observed in meninges and third ventricle walls while no binding was detected in the hypothalamic nuclei. Saturation experiments, in the anterior and posterior pituitary, revealed one specific binding site with an affinity constant (Kd) of 0.5 nM. Competition experiments were achieved using either rat IL-1 beta (rIL-1 beta) or human IL-1s (hIL-1 alpha, hIL-1 beta and IL-1 receptor antagonist: hIL-1a). Affinity constants (Ki) were drastically different according to the ligand used, while Ki values were found similar in anterior and posterior pituitary. Competition with rIL-1 beta revealed one binding affinity (Ki of 0.1 nM range). In contrast, competition with hIL-1 beta revealed two binding affinities: a high (Ki: 0.1 pM range) and a low one (Ki: 1 nM range). Competition with hIL-1ra was obtained for high concentrations only (Ki: 10-100 nM range), whereas human IL-1 alpha (hIL-1 alpha) was unable to compete at 1-100 nM.(ABSTRACT TRUNCATED AT 250 WORDS

MAPSSIC, a Novel CMOS Intracerebral Positrons Probe for Deep Brain Imaging in Awake and Freely Moving Rats: A Monte Carlo Study

International audiencePreclinical 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 CMOS 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 · Bq −1 · 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 µm would lead to an increase of positrons sensitivity by a factor of 1.74, but to a decrease of the direct (positrons) to indirect (γ-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