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

ABSTRACT: 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.

SUBMITTER: Turkman N 

PROVIDER: S-EPMC8919062 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature