Microtubule (MT) dysfunction is a hallmark of neurodegenerative diseases, tauopathies, and genetic disorders. Positron emission tomography (PET) enables the non-invasive assessment of MT dynamics in vivo, but current ¹¹C-labeled radiotracers are limited by the short half-life of carbon-11. Here, we report the radiosynthesis and in vitro evaluation of [¹⁸F]FE-MPC6827, an ¹⁸F-labeled derivative of the brain-penetrant MT-destabilizing agent MPC-6827 (verubulin). Radiosynthesis from the corresponding tosylate precursor afforded [¹⁸F]FE-MPC6827 in 60 ± 3% radiochemical yields (n = 22), >99% radiochemical purities, and molar activities up to 475 GBq/µmol. Physicochemical profiling revealed a logD_7.4 value of 3.37 ± 0.05 and favorable CNS-MPO, BBB, and CNS-PET-MPO scores, although brain permeability remains to be established experimentally. In HEK293T cells, MT destabilization significantly increased tracer accumulation, whereas MT stabilization significantly reduced uptake. Overexpression of MT-associated proteins (tau, spastin, MARK, α-tubulin) produced directionally consistent but statistically non-significant changes in tracer uptake, concordant with its effects on MT mass or stability. Across the experiments, tracer uptake correlated inversely with the markers of MT stability. These findings suggest responsiveness to changes in MT organization, although preferential binding to depolymerized tubulin remains to be confirmed by direct binding studies. Taken together, [¹⁸F]FE-MPC6827 is a promising first-in-class radiofluorinated PET tracer candidate for imaging MT dynamics in the central nervous system.

Microtubule (MT) dysfunction is a hallmark of neurodegenerative diseases, tauopathies, and genetic disorders. Positron emission tomography (PET) enables non-invasive assessment of MT dynamics in vivo, but current ¹¹C-labeled radiotracers are limited by the short half-life of carbon-11. Here, we report the radiosynthesis and in vitro evaluation of [¹⁸F]FE-MPC6827, an ¹⁸F-labeled derivative of the brain-penetrant MT-destabilizing agent MPC-6827 (verubulin). Radiosynthesis from the corresponding tosylate precursor afforded [¹⁸F]FE-MPC6827 in 60±3% radiochemical yields (n=22), >99% radiochemical purities, and molar activities up to 475 GBq/µmol. Physicochemical profiling revealed a logD_7.4 value of 3.37±0.05 and favorable CNS-MPO, BBB, and CNS-PET-MPO scores, indicating suitable properties for brain imaging. In HEK293T cells, MT destabilization significantly increased tracer accumulation, whereas MT stabilization significantly reduced uptake. Overexpression of MT-associated proteins (TAU, SPASTIN, MARK, α-tubulin) produced directionally consistent but statistically non-significant changes in tracer uptake concordant with effects on MT mass or stability. Across experiments, tracer uptake correlated inversely with MT stability. These findings suggest that [¹⁸F]FE-MPC6827 preferentially binds to depolymerized tubulin and responds to global shifts in MT dynamics, but may be less sensitive to subtle or localized cytoskeletal changes. Taken together, [¹⁸F]FE-MPC6827 is a promising first-in-class radiofluorinated PET tracer for imaging MT dynamics in the central nervous system.