Overview
flowchart TD
PSP["PSP"] -->|"associated with"| Alzheimer["Alzheimer"]
PSP["PSP"] -->|"associated with"| Als["Als"]
PSP["PSP"] -->|"associated with"| Alzheimer_s_disease["Alzheimer's disease"]
PSP["PSP"] -->|"expressed in"| neurons["neurons"]
PSP["PSP"] -->|"downregulates"| SV2A["SV2A"]
PSP["PSP"] -->|"targets"| tauopathy["tauopathy"]
PSP["PSP"] -->|"participates in"| unfolded_protein_response["unfolded protein response"]
PSP["PSP"] -->|"regulates"| STX6["STX6"]
PSP["PSP"] -->|"associated with"| frontotemporal_dementia["frontotemporal dementia"]
PSP["PSP"] -->|"participates in"| oxidative_stress_response["oxidative stress response"]
PSP["PSP"] -->|"associated with"| Parkinson_s_disease["Parkinson's disease"]
PSP["PSP"] -->|"regulates"| Parkinson_s_disease["Parkinson's disease"]
PSP["PSP"] -->|"associated with"| tauopathy["tauopathy"]
PSP["PSP"] -->|"biomarker for"| Ms["Ms"]
style PSP fill:#4fc3f7,stroke:#333,color:#000
This first-in-human study evaluates two novel 4R tau-selective PET ligands specifically designed for imaging 4-repeat tauopathies including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and Argyrophilic Grain Disease (AGD).
The study represents a critical advance in neuroimaging for tauopathies, addressing the fundamental limitation of existing tau PET tracers that show suboptimal binding to 4R tau isoforms predominant in PSP and related disorders.
Trial Details
...Overview
Mermaid diagram (expand to render)
This first-in-human study evaluates two novel 4R tau-selective PET ligands specifically designed for imaging 4-repeat tauopathies including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and Argyrophilic Grain Disease (AGD).
The study represents a critical advance in neuroimaging for tauopathies, addressing the fundamental limitation of existing tau PET tracers that show suboptimal binding to 4R tau isoforms predominant in PSP and related disorders.
Trial Details
| Parameter | Value |
|-----------|-------|
| NCT Number | NCT07348276 |
| Status | Recruiting |
| Phase | Early Phase 1 |
| Sponsor | Invicro |
| Intervention | Two novel 4R tau PET ligands |
| Purpose | First-in-human safety and evaluation |
| Study Type | Interventional |
| Allocation | Non-randomized |
Tau Biology and 4R Tauopathies
The [tau protein](/proteins/tau) is encoded by the [MAPT](/genes/mapt) gene and exists in six isoforms in the human brain, generated by alternative splicing. These isoforms differ in the presence of three or four microtubule-binding repeat domains:
- 3R tau (three repeats): Three-repeat tau isoforms are predominant in [Alzheimer's disease](/diseases/alzheimers-disease)
- 4R tau (four repeats): Four-repeat tau isoforms dominate in PSP, CBD, and AGD
The selective binding to 4R tau requires ligands with specific structural properties that recognize the additional microtubule-binding repeat domain present in 4R but not 3R isoforms.
4R Tauopathies
4R tauopathies are a group of neurodegenerative disorders characterized by accumulation of 4R tau in the brain:
- Progressive Supranuclear Palsy (PSP): Most common 4R tauopathy, affecting brainstem and subcortical structures
- Corticobasal Degeneration (CBD): Presents with asymmetric rigidity, apraxia, and cortical sensory loss
- Argyrophilic Grain Disease (AGD): Common age-related tauopathy with widespread brain involvement
Mechanism of Action
The novel 4R tau ligands are designed to:
Selectively bind 4R tau — High affinity for 4-repeat tau isoforms
Visualize PSP pathology — Target tau aggregates in affected brain regions
Differentiate from 3R tau — Unlike AV-1451 which prefers 3R/3R+4R
Minimize off-target binding — Reduce non-specific signals from monoamine oxidase bindingLigand Properties
Key properties required for an effective 4R tau PET ligand:
- High affinity and selectivity for 4R tau fibrils
- Appropriate lipophilicity for [blood-brain barrier](/entities/blood-brain-barrier) penetration
- Low non-specific binding in brain tissue
- Favorable pharmacokinetics for imaging
Rationale for PSP
Current tau PET tracers have limitations when applied to PSP:
- [18F]AV-1451 (Flortaucipir) shows lower affinity for 4R tau compared to 3R/4R combinations[@nct]
- Non-specific binding in basal ganglia regions complicates interpretation in PSP
- Limited utility in pure 4R tauopathies where 3R tau is absent
4R-selective ligands could provide:
- Better signal in PSP — Higher specific binding in affected regions
- Improved diagnostics — More accurate in vivo detection of 4R pathology
- Superior trial endpoints — Better sensitivity for detecting treatment effects
Study Design
Phase 1 First-in-Human
The trial follows a traditional first-in-human design:
- Population: Healthy volunteers and PSP patients
- Primary endpoints: Safety, tolerability, pharmacokinetics
- Secondary endpoints: Brain uptake, target binding characteristics
- Dose escalation: Ascending dose cohorts to establish optimal imaging parameters
Study Arms
The study evaluates two distinct 4R tau ligand candidates, allowing direct comparison of imaging characteristics and enabling selection of the lead compound for further development.
Imaging Protocol
Standard PET imaging protocol includes:
- Dynamic PET scanning following radiotracer injection
- Concurrent MR imaging for anatomical reference
- Standardized uptake value (SUV) calculations
- Distribution volume ratio (DVR) measurements where applicable
Clinical Significance
This trial represents an important step toward:
Better diagnostic tools — Improved in vivo tau imaging for 4R tauopathies
Trial enrichment — Select patients with confirmed tau pathology for therapeutic trials
Target engagement — Measure drug effects on tau pathology
Disease monitoring — Track disease progression with tau PET
Differential diagnosis — Help distinguish between different tauopathiesThe ability to specifically image 4R tau pathology in vivo has been a long-standing goal in neurodegenerative disease research. Current diagnostic criteria for PSP and CBD rely heavily on clinical presentation, which can be variable and overlap with other disorders. A validated 4R tau PET ligand would provide objective evidence of underlying pathology, enabling earlier and more accurate diagnosis.
| Compound | Developer | Target | Status |
|---------|-----------|--------|--------|
| PI-2620 | Life Molecular Imaging | 3R/4R tau | Phase 2 |
| PM-PBB3 | Aprinoia | 3R/4R tau | Phase 2 |
| [18F]RO948 | Roche | 3R/4R tau | Phase 1 |
| Flortaucipir (AV-1451) | Avid/Eli Lilly | 3R/4R tau | Approved for AD |
Related Pages
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Clinical Trials in PSP](/clinical-trials/progressive-supranuclear-palsy)
- [PI-2620 Tau PET](/clinical-trials/pi2620-psp-tau-pet)
- [Tau Protein](/proteins/tau)
- [MAPT Gene](/genes/mapt)
- [4R Tauopathies](/mechanisms/4r-tauopathies)
- [Tau PET Imaging](/diagnostics/tau-pet-imaging)
- [Corticobasal Degeneration](/diseases/corticobasal-degeneration)
External Links
- [ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT07348276)
References
Unknown, NCT07348276 - First-in-Human 4R Tau Ligand Study (n.d.)
Unknown, Invicro Neuroscience (n.d.)
Unknown, Flortaucipir binding in 4R tauopathies (n.d.)From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
- [Aquaporin-4 Polarization Rescue](/hypothesis/h-c8ccbee8) — <span style="color:#81c784;font-weight:600">0.67</span> · Target: AQP4
- [Microglial Purinergic Reprogramming](/hypothesis/h-5daecb6e) — <span style="color:#81c784;font-weight:600">0.66</span> · Target: P2RY12
- [Sphingolipid Metabolism Reprogramming](/hypothesis/h-6657f7cd) — <span style="color:#81c784;font-weight:600">0.61</span> · Target: CERS2
- [Complement C1q Subtype Switching](/hypothesis/h-5a55aabc) — <span style="color:#ffd54f;font-weight:600">0.59</span> · Target: C1QA
- [Glial Glycocalyx Remodeling Therapy](/hypothesis/h-c35493aa) — <span style="color:#ffd54f;font-weight:600">0.58</span> · Target: HSPG2
- [Ephrin-B2/EphB4 Axis Manipulation](/hypothesis/h-e6437136) — <span style="color:#ffd54f;font-weight:600">0.56</span> · Target: EPHB4
- [Netrin-1 Gradient Restoration](/hypothesis/h-05b8894a) — <span style="color:#ffd54f;font-weight:600">0.44</span> · Target: NTN1
Related Analyses:
- [4R-tau strain-specific spreading patterns in PSP vs CBD](/analysis/SDA-2026-04-01-gap-005) 🔄
Pathway Diagram
The following diagram shows the key molecular relationships involving First-in-Human 4R Tau Ligand Study in PSP discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)