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The design and radiosynthesis of [18F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [18F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18F-radiolabel into a phenyl ring (18F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74–1.51 GBq/µmol, 20–41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity. [ABSTRACT FROM AUTHOR]

We utilized positron emission tomography (PET) imaging in vivo to map the spatiotemporal biodistribution/expression of class-IIa histone deacetylases (class-IIa HDACs) in the central nervous system (CNS). Herein we report an improved radiosynthesis of [ 18 F]NT160 using 4-hydroxy-TEMPO which led to a significant improvement in radiochemical yield and molar activity. PET imaging with [ 18 F]NT160, a highly potent class-IIa HDAC inhibitor, led to high-quality and high-contrast images of the brain. [ 18 F]NT160 displayed excellent pharmacokinetic and imaging characteristics: brain uptake is high in gray matter regions, tissue kinetics are appropriate for a 18 F-tracer, and specific binding for class-IIa HDACs is demonstrated by self-blockade. Higher uptake with [ 18 F]NT160 was observed in the hippocampus, thalamus, and cortex while the uptake in the cerebellum was relatively low. Overall, our current studies with [ 18 F]NT160 will likely facilitate the development and clinical translation of PET tracers for imaging of class-IIa HDACs biodistribution/expression in cancer and the CNS.