| Field |
Value |
| NCT Number |
NCT03625128 |
| Status |
Completed |
| Phase |
Phase 1 |
| Sponsor |
To be verified (Taiwan/Japan collaboration) |
| Study Type |
Interventional |
| Intervention |
18F-PM-PBB3 PET imaging |
| Conditions |
PSP, CBD, AD, healthy controls |
| Sites |
Japan, Taiwan |
| Tracer Name |
18F-APN-1607, 18F-PM-PBB3 |
Positron Emission Tomography (PET) imaging of tau pathology has revolutionized our ability to visualize and quantify neurodegeneration in vivo. However, existing tau PET tracers were designed primarily for Alzheimer's disease, where 3R/4R tau (paired helical filaments) predominates.
Limitations of First-Generation Tau Tracers:
- AD-centric design: Optimized for 3R/4R tau in AD
- Off-target binding: Bind to monoamine oxidase and other proteins
- Limited 4R specificity: Poor discrimination between 3R/4R and 4R tauopathies
- Signal overflow: Signal in AD brains can saturate, limiting quantification
Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are characterized by:
- 4R tau predominance: Straight filaments instead of paired helical filaments
- Distinct regional distribution: Brainstem and basal ganglia involvement
- Different therapeutic implications: 4R-specific treatments require 4R-specific biomarkers
18F-PM-PBB3 (also known as 18F-APN-1607) represents a second-generation tau PET tracer specifically developed for 4R tauopathies:
- High affinity for 4R tau: Selective binding to straight filaments
- Low off-target binding: Reduced binding to MAO-B and other proteins
- Optimal kinetics: Fast brain uptake and clearance
- Quantifiable signal: Suitable for quantitative analysis
PM-PBB3 is a small molecule radioligand that:
- Crosses the blood-brain barrier: Lipophilic structure enables CNS penetration
- Binds selectively to tau filaments: High affinity for aggregated tau
- Emits positrons: 18F label enables PET detection
- Clears rapidly: Favorable kinetics for repeated imaging
| Property |
18F-PM-PBB3 |
| Ki for 4R tau |
~1-5 nM |
| Ki for 3R/4R tau |
~5-10 nM |
| Off-target (MAO-B) |
Low |
| Brain uptake |
High |
| Clearance |
Moderate |
Typical PET imaging with 18F-PM-PBB3 involves:
- Radiotracer injection: 185-370 MBq (5-10 mCi) IV
- Dynamic acquisition: 90-120 minutes
- Reconstruction: Standard filtered back-projection or iterative methods
- Quantification: Standardized uptake value (SUVR), distribution volume (VT)
- Primary: Evaluate safety and tolerability
- Secondary:
- Assess radiation dosimetry
- Compare uptake patterns in different tauopathies
- Correlate PET signal with clinical severity
- PSP patients: Probable PSP Richardson syndrome
- CBD patients: Clinically diagnosed CBD
- AD patients: Probable Alzheimer's disease
- Healthy controls: Age-matched individuals without neurological disease
- Baseline MRI: Structural imaging for atrophy assessment
- 18F-PM-PBB3 PET: Tau tracer imaging
- 18F-FDG PET: Metabolic imaging (optional)
- Clinical rating scales: MDS-UPDRS, PSPRS, MMSE
- Age: Typically 50-85 years
- Diagnosis: Probable PSP, CBD, or AD per established criteria
- Capacity: Able to provide informed consent
- Tolerance: Able to lie still for PET imaging
- Contraindications: MRI/PET contraindications
- Other neurological conditions: Unless healthy control
- Psychiatric conditions: Active psychosis
- Radiotracer allergies: Previous adverse reactions
| Measure |
Description |
| Adverse events |
Safety monitoring |
| Radiation dosimetry |
Effective dose estimation |
| Vital signs |
Post-injection monitoring |
| Measure |
Description |
| SUVR |
Standardized uptake value ratio |
| Regional binding |
Tau distribution in specific brain regions |
| Clinical correlation |
PET signal vs. clinical scores |
18F-PM-PBB3 enables differentiation between tauopathies:
PSP Pattern:
- Brainstem: Pontine and midbrain involvement
-
- Basal ganglia: Globus pallidus, subthalamic nucleus
-
- Cerebellum: Dentate nucleus
CBD Pattern:
- Motor cortex: Primary motor and premotor areas
-
- Parietal lobe: Posterior regions
-
- Basal ganglia: Variable involvement
AD Pattern:
-
-
-
- Posterior cingulate: Default mode network
-
- Cortical association areas
Diagnostic Accuracy
- Differentiate 4R tauopathies from 3R/4R tauopathies
- Support clinical diagnosis
- Identify atypical presentations
Patient Stratification
- Select patients for clinical trials
- Enrich biomarker-positive populations
- Exclude non-tauopathy mimics
Therapeutic Monitoring
- Track disease progression
- Monitor treatment response
- Validate biomarker endpoints
| Tracer |
Target |
Primary Use |
4R Specificity |
| 18F-AV-1451 (Flortaucipir) |
3R/4R tau |
AD |
Low |
| 18F-GTP-1 |
3R/4R tau |
AD |
Low |
| 18F-PM-PBB3 |
4R tau |
PSP/CBD |
High |
| PI-2620 |
4R tau |
PSP/CBD |
High |