Discovery of Pyrazole-Based Positron Emission Tomography Agent that Maps Histone Deacetylase 6 (HDAC6) in the...

Histone deacetylase 6 (HDAC6) is a crucial target for the development of pharmaceuticals used in the treatment of neurodegenerative disorders. Here, we identified 16a as a candidate of positron emission tomography (PET) tracer for HDAC6 imaging from pyrazole derivatives, which showed strong HDAC6 affinity (K_d = 1.66 nM) and higher accumulation in the brain of wild-type mice than in HDAC6 knockout mice. Following radiolabeling with fluorine-18, PET with [¹⁸F]16a exhibited heterogeneous uptake of radioactivity, corresponding to the biological distribution of HDAC6 in the monkey brain. These radioactive distributions were homogeneously diminished by the preadministration of ACY-775, a potent inhibitor of HDAC6, suggesting that radioactive accumulation in PET images could reflect the specific binding of [¹⁸F]16a with HDAC6. Thus, [¹⁸F]16a is a promising PET tracer for HDAC6 imaging that motivates future clinical research.