TY - JOUR T1 - <strong>Quantitative comparison of [<sup>18</sup>F]3F4AP with MRI and other PET radiotracers in a monkey with a prior traumatic brain injury</strong> JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 155 LP - 155 VL - 61 IS - supplement 1 AU - Nicolas Guehl AU - Karla Ramos-Torres AU - Clas Linnman AU - Sung-Hyun Moon AU - Maeva Dhaynaut AU - Moses Wilks AU - Paul Han AU - Chao Ma AU - Ramesh Neelamegam AU - Yu-Peng Zhou AU - Georges El Fakhri AU - Daniel Reich AU - Marc Normandin AU - Pedro Brugarolas Y1 - 2020/05/01 UR - http://jnm.snmjournals.org/content/61/supplement_1/155.abstract N2 - 155Introduction: [18F]3F4AP was recently developed for PET imaging of voltage-gated potassium channels in the brain (Kv1 family) based on the multiple sclerosis drug 4-aminopyridine (4AP, dalfampridine)1,2. Kv1 channels have been shown to increase in expression and accessibility after demyelination3-6. Since demyelination occurs after traumatic brain injuries (TBIs)7,8, the goal of this study was to investigate [18F]3F4AP in a monkey with an old TBI and compare it with the well-established tracers [18F]FDG, [11C]PBR28, [11C]PiB as well as with several MRI sequences. Methods: A rhesus monkey sustained a minor intracranial injury during a craniotomy procedure and subsequently full clinical recovery was observed. The animal was imaged on a GE Discovery MI PET/CT scanner and on an 3T Siemens Biograph mMR 3 years after the injury. [18F]3F4AP, [11C]PBR28, and [11C]PiB dynamic PET data were acquired for at least 120 min following intravenous tracer injections. Arterial blood samples were collected for [18F]3F4AP and [11C]PBR28 to determine radiotracer time courses in whole blood (WB) and plasma (PL) and radiometabolite analyses performed on a subset of PL samples to generate metabolite-corrected input functions. [18F]FDG static SUV images were acquired from 60 to 66 min post injection. Images were reconstructed using a 3D iterative reconstruction algorithm. [18F]3F4AP signal was quantified using a two-tissue compartment model (K1-k4) and regional total volume of distribution (VT) calculated as (K1/k2)(1+k3/k4). [11C]PBR28 signal was quantified with a one-tissue compartment model (K1-k2) and regional VT calculated as K1/k2. [11C]PiB signal was quantified using Logan Distribution Volume Ratio (DVR) and a 30min t* with cerebellar gray matter as a reference region. MR sequences included T1w pre- and post Gd contrast, T2w fluid-attenuated inversion recovery (FLAIR), and sequences to assess fiber integrity (diffusion tensor imaging, DTI) and myelin content (magnetization transfer ratio, MTR). A ROI of the lesion was drawn on [18F]3F4AP images and mirrored ROI positioned on the contralateral area for comparison. Results: [18F]3F4AP showed a 40.3% increase in VT in the lesion compared to the contralateral side suggestive of increased K+channel binding and possible demyelination. ROI-based quantitative analysis obtained with the other tracers showed a 16.6% reduction in [18F]FDG SUV compared to the contralateral side suggestive of hypometabolism or/and hypoperfusion. [11C]PIB demonstrated a 11.9% decrease in DVR, indicating no amyloid accumulation in the lesion but possibly some demyelination. [11C]PBR28 showed a 29.9% decrease in VT as well as a large decrease (-55.1%) in K1 suggesting reduced perfusion but no discernable inflammation. Likewise, further kinetic analyses of [18F]3F4AP and [11C]PIB indicated reduced perfusion in the lesion. MRI showed reductions on T1 (-9%), T2-FLAIR (-14%), and MTR (-15%) images and small changes in DTI measures. No contrast enhancement was observed in the lesion. Taken together, MR findings suggested an intact blood-brain barrier, gliosis, encephalomalacia and possible demyelination. ROI-based comparison of the relative changes in the injury compared to contralateral ROI showed that [18F]3F4AP PET was the most sensitive tool for detecting the lesion. Conclusions: [18F]3F4AP showed high sensitivity to what appears to be a chronic TBI in a rhesus macaque, suggestive of increased K+channel expression and plausible demyelination. Further investigation with other PET tracers showed reduced perfusion at the site of injury without inflammation or amyloid deposition and possible demyelination. Some of the MR findings (decreased MTR) were consistent with demyelination but not others (reduced T2-FLAIR). Histopathology will be performed when postmortem samples are available to understand what is driving the [18F]3F4AP uptake. Support: R01NS114066 P41EB022544 T32EB013180 S10OD0180035 ER -