Molecular imaging of peripheral and central nervous system myelin

The National Institute of Neurological Disorders and Stroke awarded Trace Biosciences Inc. $448,711 on September 3, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to develop molecular imaging agents for detecting and monitoring myelin loss in demyelinating diseases including multiple sclerosis and Charcot-Marie-Tooth disease.

Trace Biosciences is advancing a platform of myelin-specific small-molecule near-infrared fluorophores to enable high-contrast in vivo imaging of nerve tissue. The recipient has synthesized and screened over 400 oxazine-based fluorophore candidates and advanced two lead agents—LGW16-03 and IT14-63—through IND-enabling studies, demonstrating safety, pharmacokinetic robustness, and compatibility with human nerve tissue. Both compounds distinguish healthy from demyelinated tissue in the peripheral and central nervous systems with high sensitivity and directly bind myelin to report on Schwann cell and oligodendrocyte health.

Period of performance runs through August 31, 2027. Work is performed in Beaverton, Oregon. The award is structured as a Project Grant, the standard assistance type for this program.

Abstract

Demyelinating neurodegenerative diseases-including multiple sclerosis (MS) and charcot-marie- tooth disease (CMT)-affect over 6 million people globally and remain among the most debilitating and costly chronic conditions worldwide, causing over $100M in global healthcare and societal cost each year. Despite decades of drug development, these diseases continue to cause substantial neurological morbidity, in part due to our limited ability to noninvasively detect and monitor the hallmark pathological feature-myelin loss. Across all demyelinating diseases, tools that can quantify myelin integrity and monitor remyelination are critically needed to guide clinical decision-making and accelerate therapeutic development. Current clinical approaches rely on indirect, often invasive techniques that fail to capture subclinical changes or quantitative insight into demyelination and recovery. Our team has pioneered the development of a first-in-class platform of myelin- specific small-molecule fluorophores that enable high-contrast imaging of nerve tissue in vivo. Over the past decade, we have synthesized and screened >400 near-infrared (NIR) oxazine-based fluorophores, identifying lead candidates with strong affinity for myelinated nerve fibers, high signal-to-background contrast, and exceptional in vivo performance across rodent, large-animal, and human specimen models. From this platform, we have advanced two lead agents-LGW16-03 and IT14-63-through IND-enabling studies, demonstrating safety, robust pharmacokinetics, and broad compatibility with human nerve tissue. Importantly, both compounds have shown the ability to distinguish healthy from demyelinated nerve tissue in both the peripheral nervous system (PNS) and central nervous system (CNS) with high sensitivity, and recent studies confirm they directly bind myelin and can report on schwann cell and oligodendrocyte health. We have also demonstrated that fluorinated derivatives of these molecules preserve their myelin-targeting properties in vivo, supporting development of 18F-labeled pet tracers. Herein, we propose to translate these agents into a noninvasive pet imaging platform for myelin-specific assessment and quantification across CNS and PNS system diseases. In this fast-track proposal, the immediate milestones include in phase I: 1) synthesis and characterization of ≥5 fluorinated small-molecule tracer candidates, 2) evaluation of pharmacokinetic and imaging performance, and 3) selection 3 lead compounds for radiolabeling based on optimal myelin specificity, contrast, and imaging window compatibility with 18F decay; in phase II: 1) synthetic optimization of radiolabeled derivatives, 2) demonstration of diagnostic accuracy in demyelinating disease models (MS and CMT), 3) selection of a lead for clinical translation, 4) toxicology and dosimetry analyses for clinical readiness, and 5) validation of the mechanistic link between imaging contrast and myelin gene expression. Successful completion of this project will yield the first clinically translatable pet imaging platform for direct, noninvasive, and quantitative assessment of myelin integrity across both the CNS and PNS-filling a critical GAP for neurodegenerative diseases.