The development of [18F]ACI‐12589, a high affinity and selective alpha‐synuclein radiotracer, as a biomarker for Parkinson’s disease and other synucleinopathies

Abstract

AbstractBackgroundParkinson’s disease (PD) and other alpha‐synucleinopathies are characterized by the progressive accumulation of alpha‐synuclein (a‐syn) inclusions in the brain, which start in the pre‐motor stage of the disease and correlates with its severity. An imaging agent for a‐syn could allow differential diagnosis and support interventional trails. AC Immune has developed and is currently testing in a first in human (FiH) clinical trial the recently discovered compound, ACI‐12589, as a PET tracer with high affinity and selectivity for a‐syn.MethodScreening of our conformation‐specific, small‐molecular weight MorphomerTM library was followed by an iterative medicinal chemistry optimization program. The primary screening strategy included the development and use of a proprietary binding assay, that importantly involved aggregates derived from PD brain samples. Autoradiography experiments performed with human tissue samples from different alpha‐synucleinopathies provided target engagement and signal specificity data. Autoradiography techniques were also employed to assess selectivity, using tissue samples from Alzheimer’s disease or Frontotemporal lobar degeneration‐TDP donors. Selected compounds were 18F radiolabeled and evaluated for their pharmacokinetics in non‐human primates (NHPs) before proceeding to clinical studies.ResultRecent optimization efforts have led to the identification of several new, highly promising chemical scaffolds. From these, the compound ACI‐12589, has emerged with highly favorable characteristics including low nanomolar affinity and excellent target occupancy in saturation binding experiments using PD brain homogenates. Using high‐resolution autoradiography, ACI‐12589 illustrates target engagement across multiple alpha‐synucleinopathies including PD, Multiple System Atrophy, and Dementia with Lewy Bodies. In classical autoradiography experiments, ACI‐12589 demonstrates significantly higher specific signal in diseased versus non‐diseased tissue samples. Furthermore, ACI‐12589 has at least 30‐fold selectivity versus Abeta and shows no binding to Tau nor TDP‐43 aggregates. Studying [18F]ACI‐12589 in NHPs reveals rapid brain uptake and quick wash out. ACI‐12589 was considered safe in the IND‐enabling toxicology study allowing advancement into the FiH clinical study.ConclusionBased on experience with other tracers, [18F]ACI‐12589 meets the target product profile deemed necessary of a highly favorable candidate to succeed as a radiotracer for imaging a‐syn inclusions. As such, [18F]ACI‐12589 has advanced into the First in Human clinical trial in patients with Parkinson’s disease to be followed by evaluation in other alpha‐synucleinopathies.