First evaluation in multiple sclerosis using PET tracer [¹⁸F]3F4AP demonstrates heterogeneous binding across lesions

Multiple sclerosis is characterized by demyelination and axonal loss in the central nervous system. While magnetic resonance imaging (MRI) is sensitive to myelin changes, conventional sequences lack specificity and cannot reliably distinguish demyelinated lesions with varying axonal integrity. We evaluated the potential of [¹⁸F]3F4AP, a novel positron emission tomography (PET) tracer and a radiolabeled derivative of 4-aminopyridine, to provide unique insights into demyelination in multiple sclerosis.

Three people with multiple sclerosis and three healthy controls underwent 2 h dynamic PET scanning with arterial blood sampling after administration of 296 MBq of [¹⁸F]3F4AP and 3T MRI. MRI sequences included T1 Magnetization Prepared Rapid Gradient Echo (MPRAGE), T2 Fluid-Attenuated Inversion Recovery (FLAIR), and Myelin Water Imaging (MWI). Kinetic modeling assessed tracer delivery and binding in brain regions and lesions. PET findings were compared to MRI and correlated with myelin content.

[¹⁸F]3F4AP rapidly entered the brain, showing 14% higher accumulation in gray and white matter in multiple sclerosis than controls. Tracer kinetics were best described using a two-tissue compartmental model (2TCM). Logan graphical analysis provided excellent correlation with 2TCM volume of distribution (V_T) and late Standardized Uptake Value (SUV) images showed good correlation to V_T within subjects and within groups. Lesions showed more variable tracer binding compared to mirrored normal-appearing white matter (NAWM), with some lesions exhibiting high or low uptake despite similar appearance on MRI. A weak inverse correlation between tracer uptake and MWI was observed in controls but not in people with multiple sclerosis.

Despite a small sample size, [¹⁸F]3F4AP showed good reproducibility and demonstrated differences between people with multiple sclerosis and controls. Its heterogeneous binding across lesions suggests that [¹⁸F]3F4AP can differentiate lesions with and without axonal integrity, which could be very valuable for monitoring multiple sclerosis progression and evaluating remyelination therapies.

NCT04699747, Start date March 25^th, 2021.