🧫 Experiment Protocol
Clinicalproposed
SUMMARY
# TDP-43 PET Ligand Development for FTD and ALS
## Background and Rationale
# TDP-43 PET Ligand Development for FTD and ALS
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent devastating neurodegenerative diseases with substantial clinical and pathological overlap. Approximately 50% of FTD cases demonstrate TDP-43 proteinopathy as the primary pathological hallmark, while the remaining cases feature tau or FUS inclusions. Similarly, ALS presents with TDP-43 pathology
METHODOLOGY NOTES
**Phase 1: Ligand Synthesis and In Vitro Validation (Months 1-6)**
• Synthesize candidate TDP-43 PET ligands based on structural analysis of TDP-43 aggregates
• Perform autoradiography on post-mortem brain tissue from FTLD-TDP (n=20), FTLD-tau (n=20), and control subjects (n=10)
• Conduct binding affinity assays using recombinant TDP-43 aggregates (Kd determination)
• Evaluate ligand selectivity against tau, α-synuclein, and amyloid-β aggregates
• Assess blood-brain barrier penetration using in vitro models
**Phase 2: Preclinical PET Imaging (Months 7-12)**
• Radiolabel lead compounds with [¹¹C] or [¹⁸F] (n=3-5 ligands)
• Perform biodistribution studies in healthy rodents (n=6 per ligand)
• Conduct PET imaging in transgenic TDP-43 mouse models (n=8-10 per group)
• Evaluate pharmacokinetics, brain uptake, and retention patterns
• Perform ex vivo autoradiography correlation with PET signal
**Phase 3: Human Safety and Dosimetry (Months 13-18)**
• Conduct Phase I safety study in healthy