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.