Discovery of 1,2,3-triazole derivatives for multimodality PET/CT/Cryo imaging of myelination in the central nervous system

Objectives: Myelin pathology is present in many neurological conditions such as multiple sclerosis (MS) and traumatic spinal cord injury (SCI). [¹¹C]MeDAS has been demonstrated proof-of-principle for using PET as an imaging endpoint for monitoring treatment response for myelin-repair therapies. To further enhance its potential for routine clinical use, we set out to develop fluorinated analogs of MeDAS, which potentially can be radiolabeled with fluorine-18 and distributed by a central radiopharmacy and used in medical facilities that are not equipped with an on-site cyclotron.

Methods: A series of fluorinated triazole analogs of MeDAS have been designed and synthesized. Systematic structure-activity relationship (SAR) studies were conducted to identify a lead compound. Click chemistry through Cu(I)-catalyzed Huisgen cycloaddition was employed for F-18 radiolabeling. In vivo PET imaging in control and two demyelination animal models, and subsequent postmortem 3D cryoimaging were performed.

Results: Following systematic SAR studies, we identified a novel myelin-imaging agent, TAFDAS, that readily penetrates the BBB and specifically binds to myelin membranes in the brain and spinal cord. F-18 labelling was successfully achieved with high radiolabeling yield and radiochemical purity. In vivo PET imaging in the brains of Shiverer mice and control littermates confirmed that [¹⁸F]TAFDAS-PET is capable of imaging myelin deficiency or damage. Sequential [¹⁸F]TAFDAS -PET imaging and 3D cryoimaging in a contusion rat model of spinal cord injury demonstrate, for the first time, that combination of PET and cryoimaging is a new imaging tool with high sensitivity, specificity and spatial resolution.

Conclusion: [¹⁸F]TAFDAS -PET imaging is very promising and can be used as an imaging marker to monitor the changes in myelination in living subjects. Research Support: no