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Beta Microprobe

Publications

New! Read the latest publication on the Betamicroprobe, describing in details the interest of this instrument for pharmacokinetics of ¹⁸F-MPPF binding in vivo in mouse brain!

Radioactivity kinetic curves measured by b microprobe in hippocampus and cerebellum of anesthetized mice after 18F-MPPF injection.
From Desbrée A, Verdurand M, Godart J, Dubois A, Mastrippolito R, Pain F, Pinot L, Delzescaux T, Gurden H, Zimmer L, Lanièce P: The Potential of a Radiosensitive Intracerebral Probe to Monitor ¹⁸F-MPPF Binding in Mouse Hippocampus In Vivo. J Nucl Med 2008 Jun 13 (2008).

Desbrée A, Verdurand M, Godart J, Dubois A, Mastrippolito R, Pain F, Pinot L, Delzescaux T, Gurden H, Zimmer L, Lanièce P: The Potential of a Radiosensitive Intracerebral Probe to Monitor ¹⁸F-MPPF Binding in Mouse Hippocampus In Vivo J Nucl Med June (2008)
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Desbrée A, Verdurand M, Godart J, Dubois A, Mastrippolito R, Pain F, Pinot L, Delzescaux T, Gurden H, Zimmer L, Lanièce P: The Potential of a Radiosensitive Intracerebral Probe to Monitor ¹⁸F-MPPF Binding in Mouse Hippocampus In Vivo J Nucl Med June (2008)

Abstract
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.

Millet P, Moulin M, Bartoli A, Del Guerra A, Ginovart N, Lemoucheux L, Buono S, Fagret D, Charnay Y, Ibañez V: In vivo quantification of 5-HT(1A)-[(18)F]MPPF interactions in rats using the YAP-(S)PET scanner and a beta-microprobe Neuroimage March (2008)
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Millet P, Moulin M, Bartoli A, Del Guerra A, Ginovart N, Lemoucheux L, Buono S, Fagret D, Charnay Y, Ibañez V: In vivo quantification of 5-HT(1A)-[(18)F]MPPF interactions in rats using the YAP-(S)PET scanner and a beta-microprobe Neuroimage March (2008)

Abstract
We performed full modeling analysis of 5-HT(1A)-[(18)F]MPPF interactions using the beta-microprobe (beta P) and a YAP-(S)PET scanner. Sixteen Wistar rats were used for beta P (n=5) and YAP-(S)PET (n=5) acquisitions and metabolite studies (n=6). Time-concentration curves were obtained in the hippocampus, raphe dorsalis, frontal cortex and cerebellum, using three injections of [(18)F]MPPF at different specific activities. B'(max) values were estimated from a two (2T-5k)- and three (3T-7k)-tissue-compartment model with beta P and YAP-(S)PET time-concentration curves. The simplified reference tissue model (SRTM) was used to estimate binding potential (BP(SRTM)) values from data obtained with the first injection and the cerebellum as the reference region. Overall, the 3T-7k model provided a better fit than the 2T-5k model, as evaluated from AIC criteria in all experiments. The rank order of receptor density (B'max) values was as follows: hippocampus>raphe approximately frontal cortex>cerebellum. Non-negligible specific binding was observed in the cerebellum (B'max (beta P)=1.5+/-0.9 pmol/ml). Significant correlations (p<0.001) between B'max and BP(SRTM) values were evident with both beta P (r=0.895) and YAP-(S)PET (r=0.695). The YAP-(S)PET system underestimated the [18F]MPPF binding levels in brain due to limited resolution (i.e. partial volume), but led to similar conclusions.

Desbrée A, Rbah L, Langlois JB, Grenier D, Mastrippolito R, Pain F, Pinot L, Lanière P, Zimmer L, Gurden H: Simultaneous in vivo magnetic resonance imaging and radioactive measurements with the Beta-Microprobe Eur J Nucl Med Mol Imaging 34:1868 1872 November (2007)
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Desbrée A, Rbah L, Langlois JB, Grenier D, Mastrippolito R, Pain F, Pinot L, Lanière P, Zimmer L, Gurden H: Simultaneous in vivo magnetic resonance imaging and radioactive measurements with the Beta-Microprobe Eur J Nucl Med Mol Imaging 34:1868 1872 November (2007)

Abstract
PURPOSE: Multimodal instrumentation is a new technical approach allowing simultaneous and complementary in vivo recordings of complementary biological parameters. To elucidate further the physiopathological mechanisms in intact small animal models, especially for brain studies, a challenging issue is the actual coupling of magnetic resonance imaging (MRI) techniques with positron emission tomography (PET): it has been shown that running the technology for radioactive imaging in a magnet alters the spatiotemporal performance of both modalities. Thus, we propose an alternative coupling of techniques that uses the beta-MicroProbe instead of PET for local measurements of radioactivity coupled with MRI. METHODS: We simultaneously recorded local radioactivity due to [(18)F]MPPF (a 5-HT(1A) receptor PET radiotracer) binding in the hippocampus with the beta-MicroProbe and carried out anatomical MRI in the same anaesthetised rat. RESULTS: The comparison of [(18)F]MPPF kinetics obtained from animals in a magnet with kinetics from a control group outside the magnet allowed us to determine the stability of tracer biokinetic measurements over time in the magnet. We were thus able to show that the beta-MicroProbe reliably measures radioactivity in rat brains under an intense magnetic field of 7 Tesla. CONCLUSION: The biological validation of a beta-MicroProbe/MRI dual system reported here opens up a wide range of future multimodal approaches for functional and pharmacological measurements by the probe combined with various magnetic resonance technologies, including anatomical MRI, functional MRI and MR spectroscopy.

Moulin-Sallanon M, Millet P, Rousset C, Zimmer L, Debilly G, Petit JM, Cespuglio R, Magistretti P, Ibáñez V: Chloramphenicol decreases brain glucose utilization and modifies the sleep-wake cycle architecture in rats J Neurochem 93(6):1623-32 June (2005)
> Abstract
Moulin-Sallanon M, Millet P, Rousset C, Zimmer L, Debilly G, Petit JM, Cespuglio R, Magistretti P, Ibáñez V: Chloramphenicol decreases brain glucose utilization and modifies the sleep-wake cycle architecture in rats J Neurochem 93(6):1623-32 June (2005)
Abstract
We studied the effects of chloramphenicol on brain glucose utilization and sleep-wake cycles in rat. After slightly anaesthetized animals were injected with [18F]fluoro-2-deoxy-D-glucose, we acquired time-concentration curves from three radiosensitive beta microprobes inserted into the right and left frontal cortices and the cerebellum, and applied a three-compartment model to calculate the cerebral metabolic rates for glucose. The sleep-wake cycle architecture was analysed in anaesthetic-free rats by recording electroencephalographic and electromyographic signals. Although chloramphenicol is a well-established inhibitor of oxidative phosphorylation, no compensatory increase in glucose utilization was detected in frontal cortex. Instead, chloramphenicol induced a significant 23% decrease in the regional cerebral metabolic rate for glucose. Such a metabolic response indicates a potential mismatch between energy supply and neuronal activity induced by chloramphenicol administration. Regarding sleep-wake states, chloramphenicol treatment was followed by a 64% increase in waking, a 20% decrease in slow-wave sleep, and a marked 59% loss in paradoxical sleep. Spectral analysis of the electroencephalogram indicates that chloramphenicol induces long-lasting modifications of delta-band power during slow-wave sleep.
Desbrée A, Pain F, Gurden H, Zimmer L, Pinot L, Lanièce P, Mastrippolito R: Combining the radiosensitive Beta MicroProbe to nuclear magnetic resonance: theoretical approach for in vivo studies in small animals J Neurosci Methods 140(1-2):47-52 April (2004)
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Desbrée A, Pain F, Gurden H, Zimmer L, Pinot L, Lanièce P, Mastrippolito R: Combining the radiosensitive Beta MicroProbe to nuclear magnetic resonance: theoretical approach for in vivo studies in small animals J Neurosci Methods 140(1-2):47-52 April (2004)

Abstract
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.

Zimmer L, Riad M, Rbah L, Belkacem-Kahlouli A, Le Bars D, Renaud B, Descarries L: Toward brain imaging of serotonin 5-HT1A autoreceptor internalization Neuroimage 22(3):1421-6 April (2004)
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Zimmer L, Riad M, Rbah L, Belkacem-Kahlouli A, Le Bars D, Renaud B, Descarries L: Toward brain imaging of serotonin 5-HT1A autoreceptor internalization Neuroimage 22(3):1421-6 April (2004)

Abstract
Enhancing cerebral serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is a common property of antidepressant treatments and the basis for their efficacy. 5-HT1A receptors located on the cell body and dendrites of 5-HT neurons (autoreceptors) play a key role in this regard. Because they normally mediate an inhibition of neuronal firing, their desensitization is a prerequisite to the delayed enhancement of 5-HT neurotransmission upon treatment with monoamine oxidase (MAOI) inhibitors or specific serotonin reuptake inhibitors (SSRI). Using beta-sensitive microprobes in vivo, we measured a significant decrease (-30%) in binding sites for the 5-HT1A PET radioligand [18F]MPPF associated with an equivalent reduction (-34%) in the cell surface density of 5-HT1A receptor immunoreactivity (internalization), in the nucleus raphe dorsalis (autoreceptors), but not hippocampus (heteroreceptors), of rats given a single dose of the specific 5-HT1A receptor agonist, 8-OH-DPAT (0.5 mg/kg, iv). This effect was completely blocked by pretreatment with the selective 5-HT1A antagonist WAY 100635. Having ruled out that this decreased density of [18F]MPPF binding in the nucleus raphe dorsalis of 8-OH-DPAT-treated rats resulted from a local blood flow effect, we obtained autoradiographic evidence indicating that the total amount of specific binding of [18F]MPPF in tissue sections was unaffected by the 8-OH-DPAT treatment in either NRD or hippocampus. It was therefore concluded that the internalization of 5-HT1A autoreceptors accounted for the decreased binding in vivo of [18F]MPPF in the nucleus raphe dorsalis of rats treated with 8-OH-DPAT. Thus, PET imaging might provide a mean to measure 5-HT1A receptor internalization in human brain and thus assess responsiveness to antidepressant treatment. Copyright 2004 Elsevier Inc.

Riad M, Zimmer L, Rbah L, Watkins KC, Hamon M, Descarries L: Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A autoreceptors and reduces the in vivo binding of the PET radioligand [18F]MPPF in the nucleus raphe dorsalis of rat J Neurosci 9;24(23):5420-6 June (2004)
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Riad M, Zimmer L, Rbah L, Watkins KC, Hamon M, Descarries L: Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A autoreceptors and reduces the in vivo binding of the PET radioligand [18F]MPPF in the nucleus raphe dorsalis of rat J Neurosci 9;24(23):5420-6 June (2004)

Abstract
Because 5-HT1A receptors located on the soma dendrites of serotonin (5-HT) neurons normally mediate an inhibition of 5-HT firing and release, the desensitization of these autoreceptors is essential for obtaining an enhancement of 5-HT transmission after treatment with 5-HT reuptake inhibitors (SSRIs). We have demonstrated previously, using immunoelectron microscopy with specific 5-HT1A antibodies, that an internalization of 5-HT1A autoreceptors is associated with their desensitization in rats given a single dose of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Here, we examined the subcellular distribution of 5-HT1A receptors in dendrites from nucleus raphe dorsalis (NRD) (autoreceptors) and hippocampus (heteroreceptors) after acute treatment with the antidepressant SSRI, fluoxetine (10 mg/kg, i.p.). In parallel experiments, the kinetics of in vivo binding of the 5-HT1A positron emission tomography radioligand 4,2-(methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]ethylpiperazine ([18F]MPPF) was measured in these two brain regions by means of stereotaxically implanted beta microprobes. One hour after treatment, there was a 36% decrease in 5-HT1A immunogold labeling of the plasma membrane of NRD dendrites, and a concomitant increase in their cytoplasmic labeling, without any change in hippocampal dendrites. In vivo binding of [18F]MPPF was reduced by 35% in NRD and unchanged in hippocampus. Both effects were blocked by pretreatment with the 5-HT1A receptor antagonist (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide) (1 mg/kg, i.p.). In brain sections of NRD and hippocampus, [18F]MPPF autoradiographic labeling did not differ between fluoxetine- and saline-treated rats. These immunocytochemical results confirmed that internalization of 5-HT1A autoreceptors may account for their desensitization, and the microprobe results suggest that this prerequisite for antidepressant treatment efficacy could be amenable to brain imaging in humans.

Ginovart N, Sun W, Wilson AA, Houle S, Kapur S: Quantitative validation of an intracerebral beta-sensitive microprobe system to determine in vivo drug-induced receptor occupancy using [11C]raclopride in rats Synapse 52(2):89-99 January (2004)
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Ginovart N, Sun W, Wilson AA, Houle S, Kapur S: Quantitative validation of an intracerebral beta-sensitive microprobe system to determine in vivo drug-induced receptor occupancy using [11C]raclopride in rats Synapse 52(2):89-99 January (2004)

Abstract
In this study, we evaluated the potential of using a new beta-sensitive microprobe system for in vivo quantification of [11C]raclopride binding and for in vivo determination of drug-induced receptor occupancy in the rat striatum. To validate this system, an ex vivo tissue dissection method was used to corroborate in vivo beta-microprobe measurements. Our data showed that the beta-microprobe-derived [11C]raclopride binding kinetics in striatum could be quantified using a tissue compartmental model with a cerebellar reference region. Haloperidol (0.001-0.1 mg/kg; i.v.) induced a dose-dependent decrease in [11C]raclopride binding in striatum as measured using the beta-microprobe with an ED50 value of 0.013 mg/kg. Highly significant relationships (P < 0.0001) were observed, within the same animals, between in vivo and ex vivo measures of haloperidol-induced D2-receptor occupancy (r = 0.98) as well as between in vivo and ex vivo measures of [11C]raclopride binding potentials (r = 0.99). Results from pretreatment and displacement studies with unlabeled raclopride and amphetamine conformed to the effect of these drugs as observed in humans using [11C]raclopride and PET and allowed estimation of the in vivo k(off) value of raclopride to 0.025 +/- 0.004 min(-1). However, allowing the system to stabilize before measurements and shielding the photomultiplier tubes were critical for obtaining these consistent results. This study demonstrates that the beta-microprobe provides reliable measurements of [11C]raclopride binding kinetics in rodents, allows for quantitative in vivo measurements of antipsychotic drug action in brain, and represents a valid and cost-effective alternative to positron emission tomography imaging in small animals. Copyright 2004 Wiley-Liss, Inc.

Millet P, Sallanon MM, Petit JM, Charnay Y, Vallet P, Morel C, Cespuglio R, Magistretti PJ, Ibáñez V: In vivo measurement of glucose utilization in rats using a beta-microprobe: direct comparison with autoradiography J Cereb Blood Flow Metab 24(9):1015-24 April (2004)
> Abstract
Millet P, Sallanon MM, Petit JM, Charnay Y, Vallet P, Morel C, Cespuglio R, Magistretti PJ, Ibáñez V: In vivo measurement of glucose utilization in rats using a beta-microprobe: direct comparison with autoradiography J Cereb Blood Flow Metab 24(9):1015-24 April (2004)
Abstract
A new beta-microprobe (betaP) has been used to locally measure the time-concentration curve of a radiolabeled substance. The betaP, analogous to positron emission tomography methodology, is useful for in vivo animal studies because it can acquire time-concentration curves with high temporal and spatial resolution. Using [18F]fluoro-2-deoxy-D-glucose and betaP, we evaluated the reliability of the biologic parameters and we compared this method with the [14C]2-deoxy-D-glucose autoradiography. BetaP time-concentration curves in three regions of the brain were obtained from 24 rats. Four kinetic parameters (K1-k4) were estimated from 60-minute experimental periods using a three-compartment model. Best fits were obtained when the vascular fraction (Fv) was estimated simultaneously with the four kinetic parameters (K1-k4). The mean estimated Fv values were about 5.5% for the frontal cortex regions and 8.0% for the cerebellum. Correlation coefficients higher than 0.830 were observed between regional cerebral metabolic rates for glucose (rCMRglc) values obtained by betaP and autoradiography. In addition, the betaP-derived input function was similar to that obtained by manual sampling. Our findings show that reliable rCMRglc values can be obtained using betaP.
Pain F, Lanièce P, Mastrippolito R, Gervais P, Hantraye P, Besret L: Arterial input function measurement without blood sampling using a beta-microprobe in rats J Nucl Med 45(9):1577-82 April (2004)
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Pain F, Lanièce P, Mastrippolito R, Gervais P, Hantraye P, Besret L: Arterial input function measurement without blood sampling using a beta-microprobe in rats J Nucl Med 45(9):1577-82 April (2004)

Abstract
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.

Zimmer L, Rbah L, Giacomelli F, Le Bars D, Renaud B: A reduced extracellular serotonin level increases the 5-HT1A PET ligand 18F-MPPF binding in the rat hippocampus J Nucl Med 44(9):1495-501 April (2003)
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Zimmer L, Rbah L, Giacomelli F, Le Bars D, Renaud B: A reduced extracellular serotonin level increases the 5-HT1A PET ligand 18F-MPPF binding in the rat hippocampus J Nucl Med 44(9):1495-501 April (2003)

Abstract
4,2'-(Methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-fluorobenzamido]ethylpiperazine ((18)F-MPPF) is a radiotracer used in clinical PET studies for the visualization of serotonin-1A (5-HT(1A)) receptors. In a previous study, we demonstrated that a rapid enhancement of extracellular serotonin concentrations influences (18)F-MPPF-specific binding. Because endogenous serotonin is significantly decreased in some pathologies, the aim of this study was to determine whether (18)F-MPPF is sensitive to depletion of this neurotransmitter. METHODS: Using the beta-microprobe, an original beta(+)-sensitive intracerebral probe, and microdialysis, the effect of decreased serotonin on the specific binding of (18)F-MPPF to 5-HT(1A) receptors was investigated in the hippocampus of the anesthetized rat. Extracellular serotonin was pharmacologically decreased in the hippocampus after a single injection of p-ethynylphenylalanine ([p-EPA] 5 mg/kg), a new tryptophan hydroxylase inhibitor. RESULTS: Our results showed that the (18)F-MPPF-specific binding was significantly enhanced after the decrease of extracellular serotonin. These results were confirmed by the (18)F-MPPF distribution in cerebral tissues (hippocampus-to-cerebellum ratio) and by the decrease of the extracellular (18)F-MPPF collected in hippocampal dialysates. CONCLUSION: This study further supports the view that (18)F-MPPF binding potential is increased in the hippocampus if the endogenous serotonin is pharmacologically decreased after a p-EPA injection. This phenomenon will be an additional factor in the interpretation of the results from (18)F-MPPF clinical PET studies.

Zimmer L, Fournet G, Benoît J, Guillaumet G, Le Bars D: Carbon-11 labelling of 8[[3-[4-(2-[(11)C]methoxyphenyl)piperazin-1-yl]-2-hydroxypropyl]oxy]thiochroman, a presynaptic 5-HT(1A) receptor agonist, and its in vivo evaluation in anaesthetised rat and in awake cat Nucl Med Biol 30(5):541-6 April (2003)
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Zimmer L, Fournet G, Benoît J, Guillaumet G, Le Bars D: Carbon-11 labelling of 8[[3-[4-(2-[(11)C]methoxyphenyl)piperazin-1-yl]-2-hydroxypropyl]oxy]thiochroman, a presynaptic 5-HT(1A) receptor agonist, and its in vivo evaluation in anaesthetised rat and in awake cat Nucl Med Biol 30(5):541-6 April (2003)

Abstract
A new compound, 8[[3-[4-(2-[(11)C]methoxyphenyl)piperazin-1-yl]-2-hydroxypropyl]oxy]thiochroman was labeled via O-methylation with [(11)C]methyl iodide in good yield and specific activity. Original biological evaluations included (i) the study in anesthetized rat with a beta-sensitive intracerebral probe (beta-Microprobe), allowing to measure locally the kinetic of the new PET ligand, and (ii) a PET-scan on a conditioned cat maintained awake during the acquisition. In both in vivo techniques, the new ligand did not reveal any specific binding in hippocampus indicating that this radiotracer is not suitable for mapping 5HT(1A) receptors using positron emission tomography.

Rbah L, Leviel V, Zimmer L: Displacement of the PET ligand 18F-MPPF by the electrically evoked serotonin release in the rat hippocampus Synapse 49(4):239-45 April (2003)
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Rbah L, Leviel V, Zimmer L: Displacement of the PET ligand 18F-MPPF by the electrically evoked serotonin release in the rat hippocampus Synapse 49(4):239-45 April (2003)

Abstract
The effects of the electrically evoked serotonin release were evaluated on the binding of (18)F-MPPF in the hippocampus of anesthetized rats. The specific binding of (18)F-MPPF was measured by an implanted beta-microprobe and the serotonin (5-HT) extracellular concentration was measured by microdialysis under the same conditions. Our results showed that the 10-, 20-, or 30-min electrical stimulation of the raphe nucleus elicited a significant increase in extracellular 5-HT, only detectable in the presence of a 5-HT reuptake inhibitor in the perfusate (5 microM clomipramine). Interestingly, the raphe stimulations were associated with a 27-76% reversible decrease of the (18)F-MPPF specific binding in the hippocampus, but an unchanged extracellular (18)F-MPPF collected in dialysates. Considered together, these observations suggest that (18)F-MPPF binding is sensitive to 5-HT released at a neuronal level. This compartment, explored by the beta-microprobe, is probably distinct from the extracellular compartment, explored by microdialysis. Copyright 2003 Wiley-Liss, Inc.

Zimmer L, Pain F, Mauger G, Plenevaux A, Le Bars D, Mastrippolito R, Pujol JF, Renaud B, Lanièce P: The potential of the beta-Microprobe, an intracerebral radiosensitive probe, to monitor the [(18)F]MPPF binding in the rat dorsal raphe nucleus Eur J Nucl Med Mol Imaging 29(9):1237-47 April (2002)
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Zimmer L, Pain F, Mauger G, Plenevaux A, Le Bars D, Mastrippolito R, Pujol JF, Renaud B, Lanièce P: The potential of the beta-Microprobe, an intracerebral radiosensitive probe, to monitor the [(18)F]MPPF binding in the rat dorsal raphe nucleus Eur J Nucl Med Mol Imaging 29(9):1237-47 April (2002)

Abstract
The aim of this study was to demonstrate the ability of a recently developed beta(+)-range sensitive intracerebral probe (beta-Microprobe) to measure the binding kinetics of [(18)F]MPPF, a well-documented 5-HT(1A) serotoninergic receptor ligand, in the dorsal raphe nucleus (DRN) of the anaesthetised rat. This midbrain nucleus presents a high concentration of 5-HT(1A) receptors known to be implicated in the effects of antidepressants. The difficulty confronting this study lay in the fact that the dimensions of the DRN are smaller than the detection volume of the beta-Microprobe. In the first part of the study, we studied the feasibility of this measurement from a theoretical point of view by autoradiography and a Monte Carlo simulation. We determined the optimal beta-Microprobe location close to the DRN and verified that this configuration allowed accurate determination of [(18)F]MPPF specific binding in the nucleus. In the second part of our study, we measured the in vivo time-concentration curves of [(18)F]MPPF binding in the DRN in comparison with the cerebellum. The specificity of [(18)F]MPPF binding in the DRN was confirmed by its displacement after non-labelled 5-HT(1A)antagonist injection (MPPF or WAY-100635). Moreover, we verified the feasibility of using beta-Microprobe monitoring and simultaneous validation by microdialysis to study the effect of an increase in extracellular serotonin, induced by fenfluramine injection, on [(18)F]MPPF binding in the DRN. Our theoretical simulations, confirmed by our experimental results, demonstrate the ability of this new device to monitor in vivo the binding of [(18)F]MPPF in the DRN of anaesthetised rodents.

Pain F, Besret L, Vaufrey F, Grégoire MC, Pinot L, Gervais P, Ploux L, Bloch G, Mastrippolito R, Lanièce P, Hantraye P: In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution beta +-sensitive microprobe Proc Natl Acad Sci U S A 99(16):10807-12 April (2002)
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Pain F, Besret L, Vaufrey F, Grégoire MC, Pinot L, Gervais P, Ploux L, Bloch G, Mastrippolito R, Lanièce P, Hantraye P: In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution beta +-sensitive microprobe Proc Natl Acad Sci U S A 99(16):10807-12 April (2002)

Abstract
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.

Zimmer L, Hassoun W, Pain F, Bonnefoi F, Lanièce P, Mastrippolito R, Pinot L, Pujol JF, Leviel V: SIC, an intracerebral beta(+)-range-sensitive probe for radiopharmacology investigations in small laboratory animals: binding studies with (11)C-raclopride J Nucl Med 43(2):227-33 April (2002)
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Zimmer L, Hassoun W, Pain F, Bonnefoi F, Lanièce P, Mastrippolito R, Pinot L, Pujol JF, Leviel V: SIC, an intracerebral beta(+)-range-sensitive probe for radiopharmacology investigations in small laboratory animals: binding studies with (11)C-raclopride J Nucl Med 43(2):227-33 April (2002)

Abstract
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.

Zimmer L, Mauger G, Le Bars D, Bonmarchand G, Luxen A, Pujol JF: Effect of endogenous serotonin on the binding of the 5-hT1A PET ligand 18F-MPPF in the rat hippocampus: kinetic beta measurements combined with microdialysis J Neurochem 80(2):278-86 January (2002)
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Zimmer L, Mauger G, Le Bars D, Bonmarchand G, Luxen A, Pujol JF: Effect of endogenous serotonin on the binding of the 5-hT1A PET ligand 18F-MPPF in the rat hippocampus: kinetic beta measurements combined with microdialysis J Neurochem 80(2):278-86 January (2002)

Abstract
By using a combination of an original beta+-sensitive intracerebral probe and microdialysis, the effect of increased endogenous serotonin on specific binding of 18F-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamido]ethyl]piperazine] to the serotonin-1A (5-HT1A) receptors was investigated in the hippocampus of the anaesthetized rat. Our beta-sensitive probe prototype was sensitive enough to obtain specific 18F-MPPF time-activity curves in the rodent (hippocampus/cerebellum ratio approximately 2). The serotonin neuronal release was pharmacologically enhanced using fenfluramine at three different doses (1, 2 and 10 mg/kg intravenous) multiplying by 2-15 the extracellular serotonin in the hippocampus. These extracellular variations of extracellular serotonin resulted in dose-ranging decreases in 18F-MPPF-specific binding in the same rat. Our results showed for the first time that 18F-MPPF binding could be modulated by modifications of extracellular serotonin in the rat hippocampus. These results were confirmed by the enhancement of extracellular radioactivity collected in dialysates after the displacement of 18F-MPPF by fenfluramine. After modelization, 18F-MPPF binding could constitute an interesting radiotracer for positron emission tomography in evaluating the serotonin endogenous levels in limbic areas of the human brain.