Design, synthesis, biochemical evaluation, radiolabeling and in vivo imaging with high affinity class-IIa histone deacetylase inhibitor for molecular imaging and targeted therapy

Herein, we describe the design, synthesis and deciphering of the key characteristics of the structure activity relationship (SAR) of trifluoromethyloxadiazole (TFMO) bearing class-IIa HDAC inhibitors. Our medicinal chemistry campaign of 23 compounds identified compound 1 as a highly potent inhibitor with sub nM affinity to class-IIa HDAC4 isoform. Therefore, We radiolabeled compound 1 (named thereafter as NT160) with [¹⁸F]fluoride thus producing the identical [¹⁸F]-NT160 as a diagnostic tool for positron emission tomography (PET). [¹⁸F]-NT160 was produced in high radiochemical purity (>95%), moderate radiochemical yield (2-5%) and moderate molar activity in the range of 0.30-0.85 GBq/umol (8.0-23.0 mCi/umol). We also established that [¹⁸F]-NT160 can cross the blood brain barrier and bind to class-IIa HDACs in vivo. The combination of [¹⁸F]-NT160 and 1 represent a novel theranostic pair using the same molecule to enable diagnostic PET imaging with [¹⁸F]-NT160 followed by targeted therapy with NT160.