Biomedical subjects

D Le Bars

Publications and source records attributed to D Le Bars.

At least 19 recordsLinked to original sources

PubMed2005

[11C]-Methionine PET: dysembryoplastic neuroepithelial tumours compared with other epileptogenic brain neoplasms.

BACKGROUND AND OBJECTIVES: Brain tumours responsible for longstanding partial epilepsy are characterised by a high prevalence of dysembryoplastic neuroepithelial tumour (DNT), whose natural evolution is much more benign than that of gliomas. The preoperative diagnosis of DNT, which is not yet feasible on the basis of available clinical and imaging data, would help optimise the therapeutic strategy for this type of tumour. This study tested whether [(11)C]-methionine positron emission tomography (MET-PET) could help to distinguish DNTs from other epileptogenic brain tumours. METHODS: Prospective study of 27 patients with partial epilepsy of at least six months duration related to a non-rapidly progressing brain tumour on magnetic resonance imaging (MRI). A structured visual analysis, which distinguished between normal, moderately abnormal, or markedly abnormal tumour methionine uptake, as well as various regions of interest and semiquantitative measurements were conducted. RESULTS: Pathological results showed 11 DNTs (41%), 5 gangliogliomas (18%), and 11 gliomas (41%). MET-PET visual findings significantly differed between the various tumour types (p<0.0002), regardless of gadolinium enhancement on MRI, and were confirmed by semiquantitative analysis (p<0.001 for all calculated ratios). All gliomas and gangliogliomas were associated with moderately or markedly increased tumour methionine uptake, whereas 7/11 DNTs had a normal methionine uptake, including all six located in the mesiotemporal structures. No DNT presented with a marked MET-PET abnormality. CONCLUSION: Normal MET-PET findings in patient with an epileptogenic and non-rapidly progressing brain tumour are suggestive of DNT, whereas a markedly increased tumour methionine uptake makes this diagnosis unlikely.

Adolescent↗

PubMed2004

Toward brain imaging of serotonin 5-HT1A autoreceptor internalization.

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.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2004

High and low grade oligodendrogliomas (ODG): correlation of amino-acid and glucose uptakes using PET and histological classifications.

Classification and treatment strategy of oligodendrogliomas (ODG) remain controversial. Imaging relies essentially on contrast enhancement using CT or MRI. The aim of our study was to use positron emission tomography (PET) using [18F]-flurodeoxyglucose (FDG) and [11C]-L-methyl-methionine (MET) to evaluate metabolic characteristics of ODG. We studied 19 patients with proven ODG, comparing standardized uptake values (SUV) and maximal tumor/contralateral normal tissues ratios (T/N). Imaging findings were compared with WHO, Smith and Daumas-Duport classifications. Uptake of FDG was decreased only in 8 patients, independently of grading, while MET uptake was always increased. MET uptake was significantly higher for high grade tumors grouped according to Smith or Daumas-Duport classifications, while no significant difference in MET uptake was found when using WHO classification. A different correlation was found between FDG and MET uptakes in normal tissues and high grade tumors. A trend for improved progression free survival was found for tumors that lacked contrast enhancement on MRI or those showing low FDG or MET uptake. In conclusion, MET appeared more sensitive than FDG to detect proliferation in ODG. The preferential protein metabolism, already noticeable for low-grade tumor, correlated with glucose metabolism and helped to separate, in vivo, high and low grade tumors.

Adult↗

PubMed2003

Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson's disease--A [(11)C]-raclopride PET study.

CONTEXT: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. OBJECTIVE: To determine in Parkinson's disease (PD) patients using positron emission tomography (PET) and [11C]-Raclopride, whether STN stimulation induces a striatal DA release. METHODS: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [11C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [11C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. RESULTS: For PD patients, the mean [(11C]-Raclopride BP (+/- SD) were, in Off stimulation condition: 1.7 +/- 0.3 for the right caudate nucleus, 1.8 +/- 0.4 for the left caudate nucleus, 2.6 +/- 0.5 for the right putamenand 2.6 +/- 0.5 for the left putamen. In On stimulation condition: 1.7 +/- 0.4 for the right caudate nucleus, 1.9 +/- 0.5 for the left caudate nucleus, 2.8 +/- 0.7 for the right putamen and 2.7 +/- 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. CONCLUSION: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [11C]-Raclopride.

Adult↗

PubMed2003

Positron emission tomography in epileptogenic hypothalamic hamartomas.

Whether the intrinsic epileptogenicity of hypothalamic hamartomas (HH) is responsible for the entire clinical spectrum of epileptic, neuropsychological and behavioural disorders associated with HH, remains an open issue, in as much as morphologically similar HH can be associated with dramatically different seizure types and cognitive outcomes. The aim of this study was to investigate brain glucose metabolism in patients with epileptogenic HH, in an attempt to identify signs of focal cortical and subcortical dysfunction which might correlate with other clinical data. We have studied five patients with epileptogenic HH using [18F]-fluoro-desoxyglucose and positron emission tomography (FDG-PET). All our patients also underwent an optimal MRI and a video-EEG monitoring, as well as an intra-cranial EEG recording in one of them. The anatomical distribution of FDG-PET abnormalities was compared to that of interictal and ictal electroclinical findings. All five patients demonstrated focal hypometabolism, ipsilateral to the predominant EEG abnormalities and side of HH. Hypometabolic areas greatly varied between patients, but were grossly concordant with the cortical regions suspected to participate in the ictal discharges in each individual. Epileptogenic hypothalamic hamartomas are usually associated with focal cortical hypometabolism in regions which might participate in the overall HH-driven epileptic network. Whether these cortical abnormalities only reflect the propagation of ictal discharges, or a potentially independent seizure onset zone remains unknown.

Adolescent↗

PubMed2002

The potential of the beta-Microprobe, an intracerebral radiosensitive probe, to monitor the [(18)F]MPPF binding in the rat dorsal raphe nucleus.

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.

Aminopyridines↗

PubMed2002

[Nociceptors and mediators in acute inflammatory pain].

OBJECTIVE: To bring together the most recent data concerning the physiology of nociceptors at a time when there has been significant progress in the understanding of these. DATA SOURCES: References were obtained from computerised bibliographic data banks (Medline and others) and the authors' personal documents. DATA SYNTHESIS: Nociceptive impulses are generated at the periphery in unmyelinated fibres called nociceptors, the responses of which depend on the tissue environment. Numerous mediators can activate, sensitise or "wake up" nociceptor: kinins (bradykinin, kallidin and their metabolites), pro-inflammatory cytokines (TNF alpha, IL-6, IL-1 beta, IL-8), anti-inflammatory cytokines (IL-4, IL-6, IL-10, IL-12, IL-13), prostanoids (PGE2, PGI2), lipo-oxygenases (leucotrienes such LTB4 or 15-HETE), the "central mediators of the immune response" (NF-kappa B), growth factors such as neurotrophins (NGF, BDNF, NT-3 and NT-4/5), peptides (substance P, CGRP, Neurokinin A), nitric oxide, histamine, serotonin, proteases, excitatory amino acids, adrenergic amines and opioids. The release of neuromediators by primary afferent fibres in the spinal cord may be summarised by successively considering calcium channels, presynaptic receptors, excitatory amino acids and peptides. CONCLUSION: Sensitisation phenomena are not exclusively peripheral but also central in origin and these are interlinked.

Cytokines↗

PubMed2001

[Acute pain measurement in animals. Part 1].

OBJECTIVE: To describe tests of nociception which appear in the "pre-clinical" literature. DATA SOURCES: References obtained by computerized bibliographic research (Medline) and the authors' personal data. DATA SYNTHESIS: Ethical problems arising from the study of the pain in awake animals, problems arising from the choice of stimulus and stimulus parameters and the quantification of responses are presented. Pain in animals can be estimated only by examining their reactions, but at the same time, the existence of a reaction does not necessarily mean that there is a concomitant sensation. A description of the signs of pain in mammals is proposed. A noxious stimulus can be defined by its physical nature, its site of application and what has previously happened to the tissues at this site. Electrical stimulation short-circuits the process of transduction at free nerve endings and is not specific; however it has the advantage that it can be applied suddenly and briefly and thus results in synchronised signals in the relevant primary afferent fibres which can be differentiated into A delta and C fibres. Heat selectively stimulates thermoreceptors and nociceptors, but the low calorific power of conventional stimulators restricts their usefulness. Radiant sources have the disadvantage of emitting waves in the visible and the adjacent infrared spectra, for which the skin is a poor absorber and good reflector. Thermodes have the disadvantage of activating mechanoreceptors and thermoreceptors simultaneously; furthermore, their capacity for transferring heat depends on the quality of contact with skin and thus on the pressure with which they are applied. These problems can be overcome by using CO2 lasers but even today, the cost of these is a major disadvantage. Chemical stimuli differ from those mentioned above by the progressive onset of their effectiveness, their duration of action and the fact that they are of an inescapable nature. Experimental models employing chemical stimuli are undoubtedly the most similar to acute clinical pain. A wide spectrum of reactions are observed in nociceptive tests, but in almost every case they involve motor responses. After defining the ideal characteristics of a nociceptive test, tests based on the use of short duration and longer duration stimuli are presented. In tests of phasic pain, reactions are evoked by thermal (tail-flick test, hot-plate test), mechanical or electrical (flinch-jump test, vocalisation test) stimuli. Tests of tonic pain employ injections of algogenic agents intradermally (formalin test) or intraperitoneally (writhing test) or even the dilation of hollow organs. All these tests will be critically appraised in a subsequent paper [1]. CONCLUSION: The tail-flick and hot-plate tests are the most used, but there is an increasing recourse to the formalin test and tests involving foot withdrawal after mechanical stimulation.

Analgesics↗

PubMed2001

[Critical analysis of animal models of acute pain. II].

OBJECTIVE: To analyse models of acute pain in experimental animals. DATA SOURCES: References were obtained from computerised bibliographic data banks (Medline and others) and the authors' personal documents. DATA SYNTHESIS: The majority of tests permit only a measurement of threshold, whereas clinical pain is almost always prolonged. The relationships between tests of acute pain and motor activity are reviewed from a number of standpoints; in particular we consider the influence, which postural adjustments of the animal may exert on motor responses in the limbs and the significance of flexor and extensor reflexes. In analysing the problem of the sensitivity of tests, we raise the following questions: 1) what type(s) of fibres underlie the observed responses and might these be different depending on whether one is stimulating a healthy or an inflamed tissue; 2) what significance do measurements of "latency" have when a stimulus is increasing; 3) how valid are the methods of analysing the results? The influence of species and the genetic line used in tests and the specificity and predictivity of tests are considered. Finally, we review those factors, which may distort behavioural measurements in animals, notably--pharmacokinetics, interactions between heterotopic stimuli, environmental factors and related psychophysiological/psychological considerations (subjective "undesirable" phenomena, learning phenomena). We pay particular attention to related physiological functions (thermoregulation, vasomotricity, blood pressure). These considerations lead us to re-position nociception within a much larger homeostatic framework which in addition to pain, includes phenomena such as anxiety and vegetative functions. They also suggest that we should define an "effective stimulus" as one, which activates nociceptive nerve terminals after a physical stimulus, has passed through a "peripheral lens" which regulates its intensity for reasons, which are physical, albeit of biological origin. Finally they remind us that the "system of pain" forms part of a whole set of subsystems--sensory, motor, vegetative, emotional, motivational--which scientific method, being reductionist by nature, cannot study in its entirety. However one must consider results of nociceptive tests within this general context. CONCLUSION: It is only by taking the approach described in this review, that fundamental and clinical research can interact usefully.

Animals↗

PubMed2001

Effects of sufentanil and NMDA antagonists on a C-fibre reflex in the rat.

The effects of intravenous sufentanil and pre-administration of N-methyl-D-aspartate (NMDA) receptor antagonists were tested on a reflex triggered by C-fibre activation. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats either (1) with an intact neuraxis or (2) in which the brain had previously been transected at the level of the obex. All four doses of sufentanil (0.33, 0.6, 1 and 2 microg kg(-1)) elicited a depression of the reflex in a dose-dependent manner. However, following the expected depression, all doses of sufentanil elicited both facilitation of the reflex and tonic inter-stimulus discharges. The C-fibre reflex was not modified following intravenous ketamine (1 mg kg(-1)) or (+)-HA966 (5 or 10 mg kg(-1)) but, when administered 5 min before sufentanil, these drugs enhanced both the extent and the duration of the depression and strongly reduced the facilitations. In the obex-transected rats, the depressive effect of 1 microg kg(-1) sufentanil increased, while the facilitation of the C-fibre reflex and the tonic inter-stimulus discharges disappeared. Pre-administration of 10 mg kg(-1) (+)-HA966 reinforced and prolonged the depressive effect of sufentanil. These results extend previous studies suggesting the involvement of NMDA receptors in the spinal transmission of nociceptive signals. They illustrate the potential of spinal NMDA receptor blockade to both enhance the analgesic, and prevent the pro-nociceptive, effects of sufentanil.

Analgesics, Opioid↗

PubMed2001

Stage-dependent changes in the modulation of spinal nociceptive neuronal activity during the course of inflammation.

Spinal and supraspinal controls can tonically or phasically modulate the output of spinal nociceptive neurons. Alterations of these modulatory systems have been described during the acute stage of inflammation. In the present study in the rat, tonic descending controls were assessed during acute (24--48 h) and chronic (3--4 weeks) stages of monoarthritis of the ankle. The electrophysiological properties of spinal convergent neurons with ankle input were compared before and after spinalization. In a parallel series of experiments, spinal convergent neurons were recorded from the normal side in order to assess the propriospinal and supraspinal inhibitory controls triggered by nociceptive stimulation of the inflamed ankle. Tonic descending inhibition of convergent neurons with input from the inflamed ankle was enhanced during the acute stage and then decreased during the chronic stage of monoarthritis. Contralateral-induced inhibitions exhibited a similar temporal evolution. Time-dependent changes in the spinal transmission of nociceptive signals were shown by removing descending modulation in animals with monoarthritis; sensitization of spinal neurons with input from the inflamed ankle was demonstrated during the acute stage of monoarthritis, whereas a crossed transmission between inflamed and normal sides was observed during the chronic stage of the disease. These results show that dynamic and stage-dependent modifications of descending controls tend to dampen the central changes associated with inflammation.

Animals↗

PubMed2001

Animal models of nociception.

The study of pain in awake animals raises ethical, philosophical, and technical problems. We review the ethical standards for studying pain in animals and emphasize that there are scientific as well as moral reasons for keeping to them. Philosophically, there is the problem that pain cannot be monitored directly in animals but can only be estimated by examining their responses to nociceptive stimuli; however, such responses do not necessarily mean that there is a concomitant sensation. The types of nociceptive stimuli (electrical, thermal, mechanical, or chemical) that have been used in different pain models are reviewed with the conclusion that none is ideal, although chemical stimuli probably most closely mimic acute clinical pain. The monitored reactions are almost always motor responses ranging from spinal reflexes to complex behaviors. Most have the weakness that they may be associated with, or modulated by, other physiological functions. The main tests are critically reviewed in terms of their sensitivity, specificity, and predictiveness. Weaknesses are highlighted, including 1) that in most tests responses are monitored around a nociceptive threshold, whereas clinical pain is almost always more severe; 2) differences in the fashion whereby responses are evoked from healthy and inflamed tissues; and 3) problems in assessing threshold responses to stimuli, which continue to increase in intensity. It is concluded that although the neural basis of the most used tests is poorly understood, their use will be more profitable if pain is considered within, rather than apart from, the body's homeostatic mechanisms.

Analgesics↗

PubMed2000

Spatial encoding properties of subnucleus reticularis dorsalis neurons in the rat medulla.

The effect of spatial summation, produced by noxious thermal stimuli, was investigated on medullary Subnucleus Reticularis Dorsalis (SRD) neurons of anaesthetized rats. Neurons with 'whole body' receptive fields were excited by a random sequence of thermal stimuli involving four different surface areas of a hindpaw (1.9, 4.8, 7.5 and 18 cm(2)). The responses of SRD neurons progressively decrease when the area of noxious stimulation exceeded 4.8 cm(2). The shape of the stimulus-response curve closely match the shape of dorsal horn convergent neurons, previously recorded under similar experimental conditions. These results suggest that, with respect to spatial encoding properties, SRD neurons are driven by the same supraspinally-mediated inhibitory mechanisms as dorsal horn convergent neurons.

Animals↗

PubMed2000

Temporal summation and a C-fibre reflex in the rat: effects of morphine on facilitatory and inhibitory mechanisms.

In intact rats, an inhibitory mechanism counteracts the increase in excitability of a flexor reflex, which is seen in spinal animals following temporal summation of C-fibre inputs; the Rostral Ventromedial Medulla is involved in this inhibitory mechanism. Electromyographic responses elicited by electrical stimulation of the sural nerve were recorded from the biceps femoris in four types of preparations, namely intact, sham-operated, Rostral Ventromedial Medulla-lesioned and decerebrate-spinal rats. The excitability of the C-fibre reflex was tested during and following high intensity homotopic electrical conditioning stimuli. Morphine (2 mg/kg) did not significantly change the basal test response but increased the excitability of the spinal cord during conditioning. This effect was triggered by the strength of inputs, involved the Rostral Ventromedial Medulla and was probably related to some forms of motor stimulation through dopaminergic transmission. While wind-up was not reduced, the inhibition related to Diffuse Noxious Inhibitory Controls, which occurred following the conditioning period, did. In spinal animals where inhibitory mechanisms disappear, the depressive effects of morphine were unmasked for both wind-up and post-conditioning facilitations. All effects of morphine were completely reversed by naloxone.

Analgesics, Opioid↗

PubMed2000

In vivo characterization of p-[(18)F]MPPF, a fluoro analog of WAY-100635 for visualization of 5-HT(1a) receptors.

The in vivo and ex vivo distributions and the pharmacological profile of the fluorinated phenylpiperazine derivative p-[(18)F]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-fluorobenzamido]-et hyl piperazine) were evaluated in the cat brain as a potential selective antagonist for 5-HT(1A) receptors using PET. After intravenous injection of p-[(18)F]MPPF in cats, there was a rapid accumulation of radioactivity in the brain, with 4% of the total radioactivity injected present in the brain at 4 minutes postinjection. The highest uptakes of radioactivity were observed in the hippocampus and cingulate cortex, regions known to be rich in 5-HT(1A) receptors, whereas lower levels of radioactivity were observed in the cerebellum. The mean ratio of radioactivity in the hippocampus to the cerebellum was 4.29 (SD = 0.21; n = 5) from 40 to 90 minutes postinjection of p-[(18)F]MPPF. The corresponding ratio for the cingulate cortex was 3.01 (SD = 0.16; n = 5). Specific binding in the hippocampus and the cingulate cortex was markedly reduced following injection of unlabeled WAY-100635 and pindolol but was unaffected by treatment with alpha1, 5-HT(2), or reuptake inhibitor agents indicating reversibility and selectivity of p-[(18)F]MPPF binding to 5-HT(1A) receptors. Ex vivo autoradiographic study with p-[(18)F]MPPF in cat brain sections showed labeling of areas rich in 5-HT(1A) receptors with a regional brain distribution that closely matched that observed using PET. These results indicate that p-[(18)F]MPPF may be a useful candidate for noninvasive PET imaging of 5-HT(1A) receptors in the living human brain.

Aminopyridines↗

PubMed2000

Brain processing of visual sexual stimuli in human males.

Despite its critical sociobiological importance, the brain processing of visual sexual stimuli has not been characterized precisely in human beings. We used Positron Emission Tomography (PET) to investigate responses of regional cerebral blood flow (rCBF) in nine healthy males presented with visual sexual stimuli of graded intensity. Statistical Parametric Mapping was used to locate brain regions whose activation was associated with the presentation of the sexual stimuli and was correlated with markers of sexual arousal. The claustrum, a region whose function had been unclear, displayed one of the highest activations. Additionally, activations were recorded in paralimbic areas (anterior cingulate gyrus, orbito-frontal cortex), in the striatum (head of caudate nucleus, putamen), and in the posterior hypothalamus. By contrast, decreased rCBF was observed in several temporal areas. Based on these results, we propose a model of the brain processes mediating the cognitive, emotional, motivational, and autonomic components of human male sexual arousal.

Adult↗

PubMed2000

[(18)F]p-MPPF: aA radiolabeled antagonist for the study of 5-HT(1A) receptors with PET.

This paper summarizes the present status of the researches conducted with [(18)F]4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamido ]ethyl]-piperazine known as [(18)F]p-MPPF, a new 5-HT(1A) antagonist for the study of the serotonergic neurotransmission with positron emission tomography (PET). This includes chemistry, radiochemistry, animal data (rats, cats, and monkeys) with autoradiography and PET, human data with PET, toxicity, and metabolism.

Aminopyridines↗

PubMed2000

Tissue distribution, autoradiography, and metabolism of 4-(2'-methoxyphenyl)-1-[2' -[N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethyl]piperazine (p-[(18)F]MPPF), a new serotonin 5-HT(1A) antagonist for positron emission tomography: An In vivo study in rats.

The in vivo behavior of 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-[(18)F]fluorobenzamido ]ethyl]-piperazine (p-[(18)F]MPPF), a new serotonin 5-HT(1A) antagonist, was studied in awake, freely moving rats. Biodistribution studies showed that the carbon-fluorine bond was stable in vivo, that this compound was able to cross the blood-brain barrier, and that a general diffusion equilibrium could account for the availability of the tracer. The great quantity of highly polar metabolites found in plasma did not contribute to the small amounts of metabolites found in hippocampus, frontal cortex, and cerebellum. Exvivo p-[(18)F]MPPF and in vitro 8-hydroxy-2-(di-n-[(3)H]propylamino)tetralin autoradiography were compared both qualitatively and quantitatively. Qualitative evaluation proved that the same brain regions were labeled and that the p-[(18)F]MPPF labeling is (a) in total agreement with the known distribution of 5-HT(1A) receptors in rats and (b) characterized by very low nonspecific binding. Quantitative comparison demonstrated that the in vivo labeling pattern obtained with p-[(18)F]MPPF cannot be explained by differences in regional blood flow, capillary density, or permeability. The 5-HT(1A) specificity of p-[(18)F]MPPF and binding reversibility were confirmed in vivo with displacement experiments. Thus, this compound can be used to evaluate parameters characterizing 5-HT(1A) binding sites in the brain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗