Investigation of a potential new PET tracer for alpha-synuclein pathology in the brain

01.10.2018 bis 31.01.2020

Imaging misfolded alpha-synuclein (aSYN) aggregation in the human brain is one of the major challenges for an early and differential diagnosis of synucleinopathies. So far a PET tracer or imaging biomarker to noninvasively detect aSYN aggregation is still missing. Here we aim to develop a PET tracer from anle138b, a compound that has been shown to have therapeutic activity in animal models of PD by inhibiting aSYN aggregation. Optimized derivatives of anle138b with similar properties regarding selectivity and therapeutic activity based on high throughput screenings were chosen for further investigation. One showed a high affinity towards aSYN (Kd=0.3 nM) in saturation binding assays, low binding to tau fibrils (Kd=5.16 nM) and a 7-10fold lower binding to Aβ in in vitro autoradiography. We selected this compound for 11C-radiolabeling and obtained a peak SUV value of 1.8 in the mouse brain. Therefore, our goal is to further validate this promising candidate as a potential PET tracer to image aSYN aggregation in the brain. First we will determine specificity and selectivity using recombinant fibrils of aSYN, abeta and tau. We will further extract aSYN from human brain tissue homogenates and correlate binding values to levels of insoluble aSYN. Further, delivery and clearance rate of the PET tracer to the brain, as well as radiometabolites will be analyzed in mice at two time points after tracer injection. In addition, P-gp substrate determination and off-target binding will be performed. If the obtained data meet the MJFF criteria for an aSYN PET ligand, we will continue with proof of concept analysis using in vitro autoradiography in human brain slices of PD and cross-validation by IHC.