Radiosynthesis and preliminary evaluation of an 18 F-labeled Tubastatin A analogue for PET imaging of histone deacetylase 6.

Abstract

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family because of its characteristics, namely its cytoplasmic localization and ubiquitin binding. HDAC6 has been implicated in cancer metastasis and neurodegeneration. In the present study, we performed radiosynthesis and biological evaluation of a fluorine-18-labeled ligand [18 F]3, which is an analogue of the HDAC6-selective inhibitor Tubastatin A, for PET imaging. [18 F]3 was synthesized by a two-step reaction composed of 18 F-fluorination and formation of a hydroxamic acid group. IC50 values of 3 against HDAC1 and HDAC6 activities were 996 and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [18 F]3. Furthermore, bone radioactivity was stable at around 2% ID/g after injection, suggesting high tolerance to defluorination. Regarding metabolic stability, 70% of the compound was observed as the unchanged form at 30 min post injection in mouse plasma. A small animal PET study in mice showed that pre-treatment with cyclosporine A had no effect on initial brain uptake of [18 F]3, suggesting low brain uptake of [18 F]3 was not caused by the P-glycoprotein-mediated efflux. While PET imaging using [18 F]3 has a limitation with respect to neurodegenerative diseases, further studies evaluating its utility for certain cancers are worth evaluating.