A receptor-binding radiopharmaceutical for imaging of traumatic brain injury in a rodent model: [99mTc]Tc-tilmanocept

Introduction: Blood-brain barrier (BBB) disruption and subsequent neuro-inflammation occur following traumatic brain injury (TBI), resulting in a spectrum of human nervous system disorders. [Tc-99m]Tc-tilmanocept is a receptor-binding radiopharmaceutical FDA-approved for sentinel lymph node mapping. We hypothesize that after an intravenous (i.v.) injection, [Tc-99m]Tc-tilmanocept, will traverse a disrupted BBB and bind to CD206-bea ring microglial cells. Methods: Age-matched mice were divided into three groups: 5-days post TBI (n = 4), and 5-days post sham (n = 4), and naive controls (n = 4). IRDye800CW-labeled [Tc-99m]Tc-tilmanocept (0.15 nmol per gram body weight) and FITC-labeled bovine scrum albumin (FITC-B5A) were injected (i.v.) into each mouse. Mice were imaged with a high-resolution gamma camera for 45 min. Immediately after imaging, the brains were perfused with fixative, excised, imaged with a fluorescence scanner, assayed for radioactivity, and prepared for histology. Results: In vivo nuclear imaging, ex vivo fluorescence imaging, ex vivo gamma well counting, and histomicroscopy demonstrated enhanced tilmanocept uptake in the TBI region. The normalized [Tc-99m]Tc-tilmanocept uptake value from nuclear imaging and the maximum pixel intensity from fluorescence imaging of the TBI group ( 1.12 +/- 0.12 and 2288 +/- 278 a.u., respectively) were significantly (P < 0.04) higher than the sham group (0.64 0.28 and 1708 +/- 101 am., respectively) and the naive group (0.76 +/- 024 and 1643 +/- 391 a.u., respectively). The mean [Tc-99m]Tc-tilmanocept scaled uptake in the TBI brains (0.058 +/- 0.013%/g) was significantly (P < 0.010) higher than the scaled brain uptake of the sham group (0.031 +/- 0.011%/g) and higher (P 0.04) than the uptake of the naive group (0.020 +/- 0.002%/g). Fluorescence microscopy demonstrated increased uptake of the IRDye800CW-tilmanocept and ITTC-BSA in the TBI brain regions. Conclusion: [Tc-99m]Tc-tilmanocept traverses disrupted blood-brain barrier and localizes within the injured region. Advances in knowledge and implications for patient care: [Tc-99m]Tc-tilmanocept could serve as an imaging biomarker for TBI-associated neuroinflammation and any disease process that involves a disruption of the blood-brain barrier. (C) 2020 Elsevier Inc. All rights reserved.