[18F]ACI-15916 PET Alpha-Synucleinopathies Imaging Trial
Overview
flowchart TD
ACI["18F-ACI-15916 PET Tracer"]
ALPHA["Alpha-Synucleinopathies"]
ACI -->|"targets"| ALPHA
style ACI fill:#81c784,stroke:#333,color:#000
style ALPHA fill:#ef5350,stroke:#333,color:#000
[18F]ACI-15916 is a novel PET radiotracer developed by AC Immune for imaging alpha-synuclein pathology in vivo. This early Phase 1 study aims to evaluate the safety, biodistribution, and brain uptake of the tracer in patients with alpha-synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
| Field | Value |
|-------|-------|
| Trial ID | NCT06891703 |
| Phase | Early Phase 1 |
| Status | Recruiting |
| Agent | [18F]ACI-15916 |
| Target | Alpha-synuclein aggregates |
| Imaging Modality | PET |
| Sponsor | AC Immune SA |
Alpha-Synucleinopathies: Disease Spectrum
Alpha-synucleinopathies represent a group of neurodegenerative disorders characterized by intracellular aggregation of the protein alpha-synuclein into insoluble fibrils.
Diseases in This Spectrum
...[18F]ACI-15916 PET Alpha-Synucleinopathies Imaging Trial
Overview
Mermaid diagram (expand to render)
[18F]ACI-15916 is a novel PET radiotracer developed by AC Immune for imaging alpha-synuclein pathology in vivo. This early Phase 1 study aims to evaluate the safety, biodistribution, and brain uptake of the tracer in patients with alpha-synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
| Field | Value |
|-------|-------|
| Trial ID | NCT06891703 |
| Phase | Early Phase 1 |
| Status | Recruiting |
| Agent | [18F]ACI-15916 |
| Target | Alpha-synuclein aggregates |
| Imaging Modality | PET |
| Sponsor | AC Immune SA |
Alpha-Synucleinopathies: Disease Spectrum
Alpha-synucleinopathies represent a group of neurodegenerative disorders characterized by intracellular aggregation of the protein alpha-synuclein into insoluble fibrils.
Diseases in This Spectrum
| Disease | Clinical Features | Primary Pathology |
|---------|-------------------|-------------------|
| Parkinson's Disease | Resting tremor, bradykinesia, rigidity | Lewy bodies in substantia nigra |
| Dementia with Lewy Bodies | Fluctuating cognition, visual hallucinations | Cortical Lewy bodies |
| Multiple System Atrophy | Autonomic failure, cerebellar ataxia | Glial cytoplasmic inclusions |
| Pure Autonomic Failure | Orthostatic hypotension | Lewy bodies in autonomic nerves |
Alpha-Synuclein Biology
Alpha-synuclein is a 140-amino acid protein encoded by the SNCA gene:
- Native state: Unstructured, intrinsically disordered
- Physiological function: Synaptic vesicle trafficking, neurotransmitter release
- Pathological form: Beta-sheet rich aggregates (fibrils)
- Cellular locations: Cytoplasm, synapses, mitochondria
Mechanism of Action
Alpha-Synuclein Pathology Detection
Alpha-synuclein (α-syn) is a 140-amino acid protein that forms Lewy bodies and Lewy neurites in Parkinson's disease and related disorders. The [18F]ACI-15916 tracer is designed to bind selectively to pathological alpha-synuclein aggregates, enabling in vivo visualization of neurodegeneration.
Tracer Development Rationale
Current alpha-synuclein imaging challenges:
- No approved PET tracers for alpha-synuclein pathology
- Post-mortem diagnosis limits understanding of disease progression
- Need for biomarker to track therapeutic response
- Disease heterogeneity makes clinical diagnosis unreliable
[18F]ACI-15916 aims to address this gap by providing a non-invasive method to detect alpha-synuclein deposition in the living brain.
Tracer Chemistry
[18F]ACI-15916 is a small molecule radioligand:
- Radioisotope: Fluorine-18 (half-life 109.8 minutes)
- Binding site: Conformation-specific binding to β-sheet aggregates
- Selectivity: Preferential binding to pathological over monomeric α-syn
- Blood-brain barrier penetration: Optimized lipophilicity (logP ~2.5-3.5)
Alpha-Synuclein Aggregation Pathogenesis
Stepwise Aggregation Model
Initiation: Genetic (SNCA duplication/mutation) or environmental triggers
Oligomerization: Formation of soluble oligomeric intermediates
Fibrillization: Conversion to insoluble β-sheet fibrils
Inclusion formation: Lewy bodies, Lewy neurites
Propagation: Cell-to-cell spread via exosomes, tunneling nanotubesToxicity Mechanisms
| Mechanism | Description | Neuronal Effect |
|-----------|-------------|-----------------|
| Mitochondrial dysfunction | Complex I inhibition | Energy depletion |
| ER stress | Unfolded protein response | Apoptosis |
| Oxidative stress | ROS generation | Membrane damage |
| Neuroinflammation | Microglial activation | Accelerated death |
| Synaptic dysfunction | Vesicle release impairment | Connectivity loss |
| Axonal transport defects | Tau phosphorylation | Degeneration |
Braak Staging of Alpha-Synuclein Pathology
The progression of Lewy body pathology follows a predictable pattern:
| Stage | Affected Regions | Clinical Correlation |
|-------|------------------|----------------------|
| 1 | Dorsal motor nucleus, olfactory bulb | Pre-motor symptoms |
| 2 | Substantia nigra, locus coeruleus | Motor symptoms emerge |
| 3 | Mesocortex, basal forebrain | Cognitive changes |
| 4 | Temporal cortex, limbic system | Dementia onset |
| 5 | Neocortex | Advanced dementia |
| 6 | Primary sensory cortex | Severe impairment |
Study Design
Objectives
Primary Objectives:
- Evaluate safety and tolerability of [18F]ACI-15916
- Characterize biodistribution and pharmacokinetics
- Establish maximum tolerated dose
Secondary Objectives:
- Assess brain uptake and binding characteristics
- Determine optimal imaging time windows
- Compare binding in patients vs healthy controls
Patient Population
| Group | Purpose |
|-------|---------|
| Parkinson's disease patients | Target pathology presence |
| Dementia with Lewy bodies patients | Cortical involvement |
| Multiple system atrophy patients | Different α-syn aggregate type |
| Healthy controls | Baseline for comparison |
Imaging Protocol
Tracer administration: Intravenous bolus injection
Dynamic PET: 60-90 minute acquisition
CT attenuation: Anatomical localization
Blood sampling: Arterial input function
Metabolite analysis: Plasma metabolite profilingOutcome Measures
Safety Endpoints:
- Adverse event incidence
- Vital sign changes
- Laboratory parameters
- Electrocardiogram changes
Pharmacokinetic Endpoints:
- Distribution volume (VT)
- Binding potential (BPND)
- Standardized uptake value (SUV)
- Time-activity curves
Clinical Significance
Diagnostic Applications
In vivo alpha-synuclein imaging could:
Confirm clinical diagnosis:
- Differentiate PD from atypical parkinsonisms
- Distinguish DLB from Alzheimer's disease
- Validate suspected MSA vs Parkinson's disease
Disease staging:
- Quantify pathology burden
- Monitor disease progression
- Identify prodromal states
Treatment monitoring:
- Track therapeutic efficacy
- Guide treatment decisions
- Enable adaptive trial designs
Therapeutic Development
Alpha-synuclein PET enables:
Patient selection: Enrich trials with confirmed pathology
Dose selection: Optimize drug exposure
Endpoint validation: Objective measure of target engagement
Basket trials: Group by biomarker status rather than diagnosisComparison with Other Tracers
| Tracer | Target | Development Stage | Company |
|--------|--------|-------------------|---------|
| [18F]ACI-15916 | α-syn aggregates | Phase 1 | AC Immune |
| [11C]PiB | Amyloid-β | Approved | Avid/GE |
| [18F]Flortaucipir | Tau | Phase 3 | Avid/GE |
| [18F]RO948 | Tau | Phase 2 | Roche |
Related Pages
- [Alpha-Synuclein Pathway](/mechanisms/alpha-synuclein-pathway-parkinsons)
- [Alpha-Synuclein Immunotherapies](/therapeutics/alpha-synuclein-immunotherapies)
- [Lewy Body Dementia](/diseases/lewy-body-dementia)
- [Multiple System Atrophy](/diseases/multiple-system-atrophy)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [AC Immune](/companies/ac-immune)
- [Alpha-Synuclein PET Imaging Advances](/biomarkers/alpha-synuclein-pet-imaging-advances)
- [Lewy Bodies](/anatomy/lewy-bodies) - pathological inclusions
References
[AC Immune Pipeline - Alpha-Synuclein Programs](https://www.acimmune.com/pipeline)
[NCT06891703 - ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT06891703)
[Alpha-Synuclein PET Tracer Development: Current Status and Future Directions (2024)](https://pubmed.ncbi.nlm.nih.gov/38290123/)
[Alpha-Synuclein Aggregation in Neurodegeneration (2023)](https://doi.org/10.1007/s00401-023-01576-w)
[AC Immune's Alpha-Synuclein PET Tracer Shows Promise in Preclinical Studies (2024)](https://www.acimmune.com/news-events)