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Caractérisation d'un biomarqueur pour l'étude en tomographie par émission de positons des récepteurs muscariniques de type M2 pour le diagnostic précoce de la maladie d'Alzheimer

Abstract : Alzheimer’s disease (AD) has an increasingly critical impact on society from the socio-economic point of view in addition to being very burdensome for the patients themselves, their relatives and friends. Diagnosis of certitude is only at post mortem and no single biomarker has yet been found to be accurate for early in vivo diagnosis. The current available treatments are only symptomatic. The few treatments under research trials have failed to demonstrate a disease modification for either lack of actual treatment efficacy or for lack of population homogeneity and for lack of reliable in vivo biomarkers able to detect a modification. In this context, it is both urgent and necessary to identify an in vivo biomarker that enables i) the differential diagnosis of AD among other dementias and ii) the assessment of treatment efficacy as a follow up in AD patients, is clearly very noticeable. This work aims to characterize the 3-(3-(3-fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine [FP-TZTP], by use of in vitro, ex–vivo and in vivo methods in rodents, to assess whether it is a suitable biomarker for Alzheimer’s disease. An impairment of the M2 subtype of the muscarinic receptors was noticed in AD patients and clear evidences of M2 selectivity in knock out mice previously injected with the fluorinated radiotracer FP-TZTP was observed. To further characterize such M2 selectivity, we performed in vitro cell culture and ex-vivo tissue dipping studies (Results #1). Encouraged by the ex-vivo results, we went on to the in vivo world. We elected the non-invasive nuclear medicine imaging technique Positron Emission Tomography (PET) to assess the biodistribution of the [18F]FP-TZTP in rats by use of the Advanced Technology Laboratory Animal Scanner (ATLAS) developed at the National Institutes of Health, Bethesda, MD, USA (Results #4). We had first assessed the ATLAS as a legitimate tool by use of a commonly used and well known radiotracer, the [18F]fluorodeoxyglucose ([18F]FDG) (Results #2 and #3). Our studies suggest that [18F]FP-TZTP may be a biomarker for AD as it is a suitable tracer for in vivo quantification of the M2 receptors.
Keywords : Small animal PET
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Laura Ravasi. Caractérisation d'un biomarqueur pour l'étude en tomographie par émission de positons des récepteurs muscariniques de type M2 pour le diagnostic précoce de la maladie d'Alzheimer. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2011. Français. ⟨NNT : 2011LIL2S013⟩. ⟨tel-00651053⟩

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