First pre-clinical validation of fluorinated ligands for the 18F TEP diagnosis of synucleinopathies – Syn4Diag

Positron emission tomography (PET) is a unique tool for the in vivo exploration of neurodegenerative diseases characterized by the aberrant deposition of specific protein species. The aim of SYN4DIAG is to develop a PET tracer of aggregated alpha-synuclein (a-syn), as such a probe does not yet exist. This exploration will i) improve the early and differential diagnosis of PD and other synucleinopathies, ii) help establish the relationships between a-syn load and disease progression, patterns of neurodegeneration and clinical symptoms, and iii) follow and assess the potential effects of new treatments able to prevent or inhibit a-syn aggregation and deposition.
The development of such a specific PET tracer remains highly challenging for several reasons such as the structural similarities among different species of amyloid fibrils and the fact that a-syn accumulation is often accompanied by widespread and dense Aß plaques and tau deposition. In addition, the mainly intracellular localization of a-syn aggregates requires that the imaging probe must cross not only the blood-brain-barrier but also neurons or glial cell membranes. Another crucial point is the need to evaluate potential tracers using in vitro and in vivo models which faithfully reflect the pathological process that occur in humans.
In SYN4DIAG, we choose to work immediately on human material during the first steps of the screening process and candidate selection, by assessing the affinity and specificity of our new potential a-syn ligands using brain extracts enriched in either a-syn (PD brain samples) or Aß/tau (AD brain samples) aggregates. Thanks to this approach, our proposal of new chemical series will be a promising answer to this scientific challenge for human health.
The SYN4DIAG project is supported by results we recently obtained and associates the complementary skills of 4 well-recognized teams in brain PET imaging (iBrain, UMR Inserm U1253, Tours), organic chemistry (ICOA, CNRS-UMR7311, Orléans), Parkinson’s disease (IMN, CNRS-UMR 5293, Bordeaux), and a clinical team that will coordinate future human applications of new PET tracers (ToNIC, Inserm/UPS 1214, Toulouse).
The specific objectives of the proposal will focus on i) the structural optimization of new fluorinated ligands, and refinement of the structure-activity relationships (SAR) to improve affinity and selectivity for a-syn, ii) the screening of in vitro binding properties of new compounds through competition experiments with a high affinity in-house [3H]-labeled tracer that we will use on human brain homogenates enriched in specific protein aggregates, iii) the synthesis of stable precursors and [18F]-radiolabeling of best compounds, iv) the biological evaluation of [18F]-candidates in vivo in rodents including assessment of the passage through the blood-brain barrier (BBB) in normal animals, and evaluation of their in vivo binding in rodent models expressing human a-syn aggregates, v) the evaluation of [18F]-candidates using autoradiography on brain sections from patients suffering from synucleinopathies.
Thanks to the expected results of SYN4DIAG, clinicians will have available the best a-syn PET tracer that, in agreement with regulations, will be ready for first-in-human studies and then will allow to improve the diagnosis and monitoring of patients suffering from neurodegenerative disease, and to evaluate the effectiveness of current treatment or those in clinical trials.