Initial clinical scans using [¹⁸F]ACI‐12589, a novel α‐synuclein PET‐tracer

Abstract

BackgroundTo study the ability of the newly developed α‐synuclein Positron Emission Tomography (PET) tracer, [18F]ACI‐12589, created and developed by AC Immune SA, to detect α‐synuclein neuropathology in vivo, in clinically diagnosed patients with α‐synucleinopathies.MethodWe intend to scan a total of up to 50 participants with different diseases associated with α‐synuclein and age‐ and gender‐matched controls. These will include participants with Parkinson’s disease (PD), Multiple System Atrophy (MSA), Dementia with Lewy bodies (DLB), or Parkinson’s disease caused by a duplication in the α‐synuclein gene, in addition to neurologically healthy volunteers. At the time of abstract submission, 23 participants have undergone [18F]ACI‐12589 PET scans. 20 scans consist of 0‐90 min dynamic scans with arterial blood sampling for blood input activity and metabolite analysis, two are full dynamic scans and one a 60‐90 min static scan without blood sampling. In addition, participants have undergone structural MRI, DaTscan or [18F]DOPA PET, and cognitive and motor testing (UPDRS‐III).ResultThe data are currently being processed and analyzed. Initial image analyses suggest that there is ACI‐12589 retention in brain areas affected by the disease process (such as the basal ganglia and cerebellar white matter) in participants with MSA, but also a potential age‐dependent retention in the basal ganglia and brain stem of controls.ConclusionWe will be presenting initial promising clinical data on the novel α‐synuclein PET tracer [18F]ACI‐12589, the initial analysis of which suggests tracer binding consistent with expected patterns of α‐synuclein pathology based on clinical manifestations. Further analyses are ongoing and our updated findings will be presented at the conference.

[11C]MODAG 005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain

“…In Alzheimer's disease (AD), the development of PET tracers targeting amyloid-β (Aβ) and tau aggregates has greatly advanced our understanding of the time course of aggregation and the regional spread of pathology, revolutionizing the early diagnosis of AD and the assessment of therapeutic effects. Several small molecules targeting αSYN aggregates have been developed over the past decade, with two of them being studied in human subjects [4][5][6][7]. Nonetheless, none of these molecules has been translated into clinical applications so far.…”

Development of Pyridothiophene Compounds for PET Imaging of α‐Synuclein

“…[14] During the preparation of this manuscript, the development of an αsyn PET radiopharmaceutical was reported, [ 18 F]ACI-12589, which bound to brain regions affected by α-synuclein pathology in patients with MSA; however, there was limited binding in PD. [15] The development of α-syn PET tracers for PD remains to be amongst the greatest challenges in PET neuroimaging and is hampered by several factors: First, the density of aggregated α-syn is low; about 10-50 times lower than the density of other protein aggregates such as amyloid beta (Aß). Therefore, a successful tracer needs to have a very high binding affinity (likely < 1 nM) to increase the specific binding signal.…”

“…However, to date, none of these tracers have proven ideal for PET imaging of PD patients [14] . During the preparation of this manuscript, the development of an α‐syn PET radiopharmaceutical was reported, [ 18 F]ACI‐12589, which bound to brain regions affected by α‐synuclein pathology in patients with MSA; however, there was limited binding in PD [15] …”

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, 4-repeat/full-length tau and alpha-synuclein

“…Alzheimer's disease (AD) is pathologically hallmarked by amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. Other tauopathies include frontotemporal dementia with 4R and 3R tau, progressive supranuclear palsy (PSP) with 4R tau, and corticobasal degeneration (CBD) with 3R tau accumulation (Spillantini and Goedert, 2013). α-synucleinopathy is characterized by the accumulation of alpha-synuclein (αSyn) in Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA).…”

“…Currently, there is an unmet clinical need for PET ligands for 4-repeat tau and αSyn aggregates to assist in diagnostic and clinical outcome evaluations. Several imaging ligands are currently in the pipeline, such as [ 18 F]ACI-12589 (Smith et al, 2022), [ 11 C]MODAG-001 (Kuebler et al, 2021), [ 18 F]SPAL-T-06 (Matsuoka et al, 2022) and [ 18 F]UCB-2897 (NCT05274568). In addition, optical imaging ligands have been developed and applied in mechanistic and treatment studies using disease animal models recapitulating amyloidosis/tauopathy/αSyn.…”