Description du projet
La TEP pour le diagnostic de la schizophrénie
Le diagnostic de la schizophrénie est un défi médical de taille du fait de l’absence de biomarqueurs spécifiques. Même si des preuves suggèrent une expression différentielle des récepteurs de l’acide gamma‑aminobutyrique (GABA) dans le cerveau des patients souffrant d’un trouble mental, ces informations proviennent d’études post‑mortem. Ainsi, les scientifiques du projet GABARPET, financé par l’UE, proposent de développer des sondes de tomographie par émission de positrons (TEP) capables de révéler des informations quantitatives sur l’expression spécifique des sous‑unités de récepteurs GABAA. Afin de surmonter l’imperméabilité de la barrière hémato‑encéphalique, ces sondes de TEP seront conçues comme des anticorps bispécifiques qui ciblent les récepteurs GABAA et les récepteurs de la transferrine. Les résultats apporteront des informations fondamentales sur la biologie de la schizophrénie et permettront d’améliorer le diagnostic de cette maladie.
Objectif
Changes in GABA receptors are known hallmarks for numerous neurological diseases including schizophrenia which is a severe psychiatric disorder that has a profound effect on both the individuals affected and society. The diagnosis of schizophrenia is complex because of the loss of high specific biomarkers. Research papers have suggested that the differential expression of GABAA receptors in the brain is associated with this mental disease. The current evidence on GABAergic abnormalities in schizophrenia is mostly based on postmortem studies and, in this sense, in vivo measurements of GABAA receptor subunits can reveal additional insights.
This project will develop Positron Emission Tomography (PET) probes which could unveil quantitative information about GABAA receptor expression in schizophrenia patients. However, the lack of imaging tracers with high affinity and specificity do not shed a clear light on the diagnosis in a traditional PET setting. In this sense, the immune-positron emission tomography (immunoPET) is a non-invasive technology based in antibody imaging which reveals a specific and sensitive molecular characterization of the cell surface phenotype in vivo. Nevertheless, its success in neuroimage is limited because of intact antibodies cannot penetrate the Brain Blood Barrier (BBB) in healthy conditions. However, GABARPET will tap into a small recombinant bispecific antibody construct targeting the GABAA receptors as well as the transferrin receptor because it is able to readily transmigrate across the BBB in vivo after peripheral injection.
This project wants to develop di-single-chain variable fragment (di-scFv) directed to α1 and α2 subunits of GABAA receptors. Then, they will be labeled with conventional radionuclides produced by cyclotron as 18F and 89Zr. ImmunoPET probes will be used in wild-type mice, GABAA receptor knockout mice and different kind of rodent models of schizophrenia.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
20014 Turku
Finlande