TDP-43 PET Ligand Development for FTD and ALS

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

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