Positron Emission Tomography (PET) imaging is a powerful molecular imaging technique that enables visualization and quantification of pathological processes in the living brain. PET has become indispensable for diagnosing neurodegenerative diseases, tracking disease progression, and evaluating therapeutic efficacy in clinical trials.
- Radioactive tracer: Patient receives positron-emitting radiopharmaceutical
- Positron emission: Radioactive decay releases positrons
- Annihilation: Positrons collide with electrons, producing gamma rays
- Detection: Ring of detectors captures gamma photon pairs
- Reconstruction: Tomographic algorithms create 3D images
- Half-life: Determines imaging window (e.g., F-18: 110 min, C-11: 20 min)
- Specificity: Binding affinity for target of interest
- Blood-brain barrier penetration: Essential for CNS applications
- Signal-to-noise: Clear distinction between target and background
- Target: Amyloid-beta plaques
- Binding: Beta-sheet structures
- Status: FDA approved for Alzheimer's diagnosis
- Clinical use: Distinguishing AD from other dementias
- Target: Amyloid plaques
- Status: Approved in Europe and FDA conditional
- Strengths: High specificity for amyloid
- Target: Amyloid plaques
- Research: Widely used in research settings
- Limitations: Short half-life (C-11)
- Target: Tau aggregates
- Properties: High affinity, good kinetics
- Research: Widely used in trials
- Target: Tau pathology
- Development: Clinical trials ongoing
- UCB-J (NeuraTrace): SV2A imaging for synaptic density
- Clinical use: Tracking neurodegeneration
- Advantage: Direct measure of neuronal loss
- PK11195: First-generation TSPO ligand
- PBR28: Second-generation with improved binding
- Target: Activated microglia
- Challenge: Genetic variability in binding
- Target: Dopamine synthesis capacity
- Use: Parkinson's disease diagnosis
- Clinical: Differentiating PD from other parkinsonisms
- Target: Dopamine transporter
- Status: FDA approved
- Clinical: Differentiating essential tremor from PD
- Target: D2 dopamine receptors
- Use: Dopamine release studies
Alpha-synuclein PET imaging represents one of the most significant unmet needs in neurodegenerative disease diagnostics. Unlike amyloid and tau PET, which have FDA-approved tracers, alpha-synuclein PET has historically lagged behind. At AD/PD 2026 in Copenhagen (March 17-21, 2026), researchers announced that a new generation of alpha-synuclein PET tracers has entered human testing — marking a major milestone for Parkinson's disease and synucleinopathy diagnostics.
- Human testing milestone: Multiple alpha-synuclein PET tracers presented early PET imaging studies in people with different synucleinopathies (Parkinson's disease, Dementia with Lewy Bodies, Multiple System Atrophy)
- Target validation: Tracers designed to bind to alpha-synuclein aggregates in vivo, enabling visualization of Lewy body pathology
- Differentiation potential: Early data suggests tracers may help distinguish between different synucleinopathies based on regional binding patterns
¶ Tracer Development Landscape
| Company/Developer |
Tracer |
Stage |
Notes |
| MODAG |
Novel α-syn PET tracer |
Phase I |
Presented at AD/PD 2026 |
| Various academic groups |
Multiple candidates |
Phase I/II |
Early human imaging studies |
| Industry consortia |
Next-gen tracers |
Preclinical |
Optimizing specificity |
Developing alpha-synuclein PET tracers is particularly challenging because:
- Alpha-synuclein aggregates exist in multiple morphologies (fibrils, oligomers, membranes)
- Non-specific binding to other proteins can confound signal
- Lower abundance compared to amyloid plaques requires higher sensitivity
- Species differences in tracer validation
Once validated, alpha-synuclein PET will enable:
- Differential diagnosis: Distinguishing PD from other parkinsonisms (MSA, PSP)
- DLB confirmation: Visualizing cortical Lewy body burden
- Disease staging: Tracking alpha-synuclein spread through Braak stages in vivo
- Clinical trials: Enrollment criteria and target engagement for alpha-synuclein therapies
- Progression monitoring: Measuring pathological spread over time
- Target: MAO-B in astrocytes
- Example: PBR111
- Use: Neuroinflammation assessment
- Example: WAY-100635
- Use: Serotonergic dysfunction in AD
- Quantitative: Provides numerical measures of pathology
- Molecular specificity: Visualizes specific proteins/processes
- Longitudinal tracking: Can monitor disease progression
- Clinical trials: Enables biomarker-driven studies
- Early detection: Can identify pathology before symptoms
- Radiopharmaceutical production: Requires cyclotron and chemistry expertise
- Cost: Equipment and tracer production expensive
- Radiation exposure: Limited repeat imaging
- Partial volume effects: Small structures underestimated
- Non-specific binding: Background signal can confound results
- Biomarker validation: Some tracers lack proven clinical utility
- Differential diagnosis: Distinguishing between dementia types
- Parkinsonism: Differentiating PD from PSP, MSA
- Preclinical detection: Identifying at-risk individuals
- Amyloid burden: Correlates with disease severity
- Tau spread: Tracks Braak staging in vivo
- Disease progression: Longitudinal imaging studies
- Enrollment criteria: Selecting amyloid-positive patients
- Target engagement: Demonstrating drug binding
- Treatment response: Measuring pathological changes
- Florbetapir (Amyvid): Amyloid imaging
- Florbetaben: Amyloid imaging
- Flortaucipir (Tauvid): Tau imaging
- F-DOPA: Dopamine imaging
- FP-CIT (DaTscan): Dopamine transporter imaging
| Target |
Tracers |
Stage |
| Tau |
Multiple |
Phase II/III |
| Synaptic density |
UCB-J |
Clinical |
| Alpha-synuclein |
Multiple |
Phase I (human testing) |
| TDP-43 |
Early development |
Preclinical |
March 2026 update: At AD/PD 2026, researchers announced that a new generation of alpha-synuclein PET tracers has entered human testing, marking a major milestone for synucleinopathy diagnostics.
¶ Companies and Institutions
- Avid Radiopharmaceuticals (Eli Lilly): Florbetapir, Flortaucipir
- GE Healthcare: Various tracers
- Siemens: Tracer development
- PerkinElmer: Research tracers
- Washington University: PET tracer development
- UCLA: Amyloid and tau imaging
- University of Pennsylvania: Neuroinflammation imaging
- Karolinska Institute: Dopamine imaging
- Alzheimer's Disease Neuroimaging Initiative (ADNI): PET imaging protocols
- Michael J. Fox Foundation: Parkinson's imaging biomarkers
- Centres for Tau Program: Tau tracer validation
¶ PET/CT and PET/MRI
- Standard: Most common hybrid system
- Advantages: CT provides anatomical reference
- Limitations: Radiation from CT
- Emerging: Growing clinical adoption
- Advantages: No additional radiation, better soft tissue
- Challenges: More complex operation
- Alpha-synuclein: Critical for Parkinson's, DLB
- TDP-43: For ALS, FTD
- alpha-Synuclein seeds: Detecting prion-like spread
- Total-body PET: Faster, lower dose imaging
- Kinetic modeling: Improved quantification
- Artificial intelligence: Image enhancement, analysis
- PET/MRI hybrid imaging
- Theranostics: Diagnostic + therapeutic
- Multi-tracer protocols
| Modality |
Spatial Resolution |
Molecular Info |
Cost |
Radiation |
| PET |
4-5 mm |
High |
High |
High |
| MRI |
1 mm |
Medium |
Medium |
None |
| CT |
1 mm |
Low |
Medium |
Medium |
| SPECT |
8-10 mm |
Medium |
Low |
Medium |