Imaging Traumatic Brain Injuries in Mice with Potassium Channel PET Tracer 18 F3F4AP

Traumatic brain injury (TBI) can lead to secondary injuries, including axon and myelin damage, which contributes to long-term neurological deficits. The positron emission tomography (PET) tracer 18F3F4AP, a fluorinated derivative of the U.S. Food and Drug Administration (FDA)-approved drug 4-aminopyridine, selectively binds to voltage-gated potassium (KV) channels, offering a novel approach to assess TBI-related node of Ranvier disruption and demyelination. This study evaluated 18F3F4AP PET in penetrating and non-penetrating TBI models. Either controlled cortical impact (CCI, penetrating) or concussive (non-penetrating) TBI models were used to induce TBI in mice. Dynamic PET imaging with 18F3F4AP was performed at time points of 0, 3, 7, 14, and/or 28-31 days post-injury (dpi), with quantitative analyses comparing tracer uptake in injured versus control regions. Luxol fast blue staining was conducted to evaluate histological myelin loss. In the CCI model, 18F3F4AP PET imaging demonstrated a 31% increase in tracer uptake at the injury site at 7 dpi, correlating with histological evidence of demyelination. Tracer uptake gradually declined over time, reflecting potential remyelination. The concussive TBI model showed a smaller and more diffuse increase in uptake at 7 dpi compared to CCI. 18F3F4AP PET imaging effectively detects demyelination following TBI with a very high sensitivity to penetrating injuries. These findings highlight the potential of 18F3F4AP as a valuable imaging biomarker for the assessment of TBI progression and/or therapeutic response. Further studies are warranted to explore its clinical applicability and comparison with other imaging modalities.