A Dual PET Imaging Technique for In Vivo Characterization of Myelination in Multiple Sclerosis

Purpose: Multiple sclerosis (MS) is an autoimmune disease characteristic of multifocal inflammatory demyelination in the brain and spinal cord. To facilitate development of novel therapies aimed at myelin repair, it is necessary to develop a direct imaging marker that is specific for changes in myelin content. For this reason, we set out to develop myelin-imaging agents for positron emission tomography (PET). These efforts have led to the development of two radiotracers for PET imaging of myelin changes. One radiotracer, termed MeDAS, targets directly to myelin membranes, the other radiotracer, termed [¹⁸F]3-F-4-AP targets axonal potassium channels underneath myelin that become exposed after demyelination. These two radiotracers complement each other and can be used in combination to provide a definitive and accurate measurement of myelin changes. In this work, we reported in vivo cross- validation of [¹⁸F]3-F-4-AP and [¹¹C]MeDAS PET imaging in the brain and spinal cord using 4 different rat models.

Methods: 1) Conduct microPET/CT imaging to detect and quantify demyelination in SCI rat model; 2) Conduct microPET/CT imaging to detect and quantify demyelination in the spinal cord in a rat model of focal demyelination induced by LPC; 3) Conduct microPET/CT imaging in an EAE rat model to detect and quantify demyelination in the brain and spinal cord; and 4) Conduct in vitro staining and ex vivo autoradiography to determine imaging specificity for myelin following microPET/CT imaging.

Results: 1) Quantitative analysis of [¹¹C]MeDAS-PET and [¹⁸F]3-F-4-AP-PET in the same animals showed significantly decreased uptake of [¹¹C]MeDAS and characteristic augments of of [¹⁸F]3-F-4-AP at the contusion site in a rat model of SCI. In comparison, no distinct decrease of [¹¹C]MeDAS uptake or increase of [¹⁸F]3-F-4-AP uptake was observed in the neighboring intact region of the spinal cord. 2) Cross-sectional staining of myelin sheaths revealed significant atrophy and demyelination at the epicenter of contusion injury, which is confirmed by both Black-Gold and conventional Luxol Fast Blue (LFB) and autoradiography in adjacent sections. 3) in an EAE rat model, [¹¹C]MeDAS-PETshowed decreased uptake of [¹¹C]MeDAS in the T12-L1 region of the spinal cord while [¹⁸F]3-F-4-AP-PET of the same animals showed increased uptake [¹⁸F]3-F-4-AP was found significantly higher in the same region. Conclusion: [¹¹C]MeDAS-PET and 3-[¹⁸F]-4-AP-PET imaging are well correlated, which can be used for cross-validation for imaging of demyelination in the spinal cord.