CE17 - Recherche translationnelle en santé

Ligands for Nuclear Imaging of Tau protein Oligomers – LINOTTE

Submission summary

Alzheimer’s disease (AD) consists of a continuum from an asymptomatic preclinical form to the disease objectivated by cognitive and memory tests. Differential diagnosis is difficult during the asymptomatic preclinical phase of the pathology. Alzheimer's disease is defined by the association of a progressive dementia syndrome and of two main characteristic brain molecular lesions: extracellular senile plaques composed primarily of amyloid peptides, and neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau aggregates. Recently a major role for extracellular pathological forms of Tau proteins, Tau oligomers, has been shown in the propagation mechanism of the pathology within the brain by contaminating neuron after neuron. Cognitive impairment becomes manifest when lesions reach the hippocampus, with abundant neocortical Tau inclusions and extracellular amyloid deposits. The development of new therapeutic strategies to eliminate the pathological forms of tau protein requires their evaluation during preclinical and clinical trials in well-characterized patient groups. Furthermore, early diagnosis is required for implementing appropriate therapy. Our project concerns the development of nuclear imaging tools to detect the early abnormal forms of Tau in the human brain with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) in order to improve the diagnosis and the follow-up of AD hallmarks. Our strategy is to develop radiolabeled nanobodies (Nbs) directed against the oligomeric form of pathologic Tau protein. Nbs represent the smallest possible (15 kDa) functional immunoglobulin-like antigen-binding fragments, possess nanomolar affinity and are by nature present in camelids. We produced a Nb (2C5), with both good affinity and specificity for human tau protein oligomers. We significantly increased the passage of the blood-brain barrier (BBB) from 2C5, as demonstrated in vitro in an artificial BBB model, by improving its isolectric point and lipophilicity and by associating it with peptides facilitating the BBB crossing. The purpose of our project is to validate in vivo this new ligand of early pathological forms of tau. The vectorized Nb will be radiolabeled, with 99m technetium (99mTc) by coordination according to the method developed in the laboratory for other Nbs. Binding properties of this radioligand will be evaluated in vitro as previously for 2C5. Then, its biodistribution will be assessed in wild-type mice to determine the radiotracer retention in the various organs. The radiotracer will then be validated in transgenic mice along SPECT imaging studies. Secondarily, the development of radiolabeling of this Nb with 68 Gallium (68Ga) will be carried out and pharmacokinetic and PET imaging studies conducted as for the 99mTc-ligand. The 99mTc and 68Ga radiolabeled ligands will finally be compared to 18F-AV1451, the most currently used NFTs radiotracer: The main goal of this project is to provide a radiotracer specific for abnormal forms of Tau usable in Nuclear Medicine facilities for SPECT and/or PET imaging.

Project coordination

PASCALE PERRET (RADIOPHARMACEUTIQUES BIOCLINIQUES UMR_S1039)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

TIMC-IMAG Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble
LRB RADIOPHARMACEUTIQUES BIOCLINIQUES UMR_S1039

Help of the ANR 348,278 euros
Beginning and duration of the scientific project: December 2020 - 24 Months

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