Products Cited in Publications Worldwide The development of a PET Radiotracer for Imaging Alpha Synuclein Aggregates in Parkinson's Disease

The development of a PET Radiotracer for Imaging Alpha Synuclein Aggregates in Parkinson's Disease

Tian, Guilong; Hsieh, Chia-Ju; Guarino, Dinahlee Saturnino; Graham, Thomas; Lengyel-Zhand, Zsofia; Schmitz, Alexander; Chia, Wai-Kit; Young, Anthony; Crosby, John-Grey; Plakas, Konstantinos

DOI:

Abstract

M503-1619 was identified as a promising ligand for positron emission tomography (PET) imaging of α-synuclein (α-Syn) pathology in Parkinson’s disease (PD). An Exemplar for binding site 9 (residues GLY-86, ILE-88, PHE-94 and LYS-96) of α-Syn fibrils was generated. An in silico ultrahigh throughput screening campaign was conducted using a 42 million compound library. Secondary in silico methods followed by visual inspection were used to select 6 compounds as candidates for in vitro binding studies. M503-1619 was found to have a high binding affinity (Ki = 6.5 nM versus the site 9 radioligand [3H]BF-2846) to α-Syn fibrils and low affinity for beta amyloid (Ki = 390 nM versus [3H]PiB) in competition binding assays. Saturation binding assays of [3H]M503-1619 in human tissues confirmed its high affinity to α-Syn (PD tissue, KD = 2.5 nM; Alzheimer's disease tissue, KD = 37 nM; progressive supranuclear palsy tissue, KD = 55 nM). Autoradiography studies demonstrated a higher binding of this radioligand in PD brain sections than in multiple system atrophy brain sections. PET studies with [11C]M503- 1619 showed high brain uptake and rapid washout (whole brain peak to 60 min ratio = 3.2) in non-human primates. The results of this study suggest that [11C]M503-1619 is a lead compound for radiotracer development imaging α-Syn with PET.

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