Advancing Neurodegenerative Diagnostics: The Role of TDP-43 PET Tracer ACI-19626

AC Immune has introduced ACI-19626, a first-in-class TDP-43 PET tracer that could change diagnosis and trial design by enabling in vivo imaging of aggregated TDP‑43 in neurodegenerative disease.

The company reports preclinical characterization published alongside a Nature Communications paper and frames the immediate clinical implication as a new capability to visualize aggregated TDP‑43 in living brain tissue—potentially altering differential diagnosis and patient selection for trials.

So what evidence supports the specificity of ACI-19626? Preclinical assays show high affinity for pathological TDP‑43 aggregates with minimal binding to physiological TDP‑43 and strong discrimination from common co‑pathologies (Aβ, tau, α‑synuclein). Autoradiography, biochemical binding panels and non‑human primate PET studies support rapid brain uptake and fast washout in target‑free regions. The authors report no off‑target activity across a panel of >100 receptors and transporters; these findings are summarized in the company report.

The press summary lists assay types and PK descriptors but omits key quantitative endpoints (for example, KD or IC50 values, exact sample sizes, autoradiography signal‑to‑background ratios, non‑human primate SUV/time or AUC values, and detailed receptor‑panel percent‑inhibition results).

So how could ACI-19626 improve neurodegenerative disease diagnosis? An imaging signal selective for aggregated TDP‑43 could enable earlier detection of TDP‑43 proteinopathy and clearer differentiation among ALS, FTD and Alzheimer’s disease with mixed pathology—sharpening clinical phenotyping and trial eligibility. Because PET documents regional target distribution and longitudinal change, ACI-19626 could reduce cohort heterogeneity, permit biomarker‑driven inclusion criteria and serve as a PET endpoint for target engagement in TDP‑43‑directed interventions, potentially allowing smaller, more focused proof‑of‑concept trials.

However, key uncertainties remain. Human translation of preclinical selectivity, scalable radiochemistry and manufacturing, potential off‑target or age‑related signal in older adults with mixed proteinopathies, and formal regulatory qualification for use in trials all need evaluation.

But a pragmatic roadmap is clear: first‑in‑human safety and dosimetry studies, blinded cross‑validation against neuropathology or CSF markers, standardized multisite PET acquisition with centralized reads, and prospective pilot enrichment studies—steps that will determine whether the preclinical promise becomes a validated clinical biomarker.

Key Takeaways:

• ACI‑19626 provides a preclinical, first‑in‑class imaging signal for aggregated TDP‑43—implication: researchers and trialists gain a potential PET biomarker to identify TDP‑43 proteinopathies.
• Patients with suspected ALS, FTD and Alzheimer’s disease with mixed pathology—implication: clearer differential diagnosis and improved eligibility stratification for trials targeting TDP‑43 biology.
• Expect first‑in‑human readouts and early trial enrichment protocols; near‑term operational needs include tracer manufacturing scale‑up, centralized PET reading pipelines, and correlation studies with CSF and neuropathology.