Radiosynthesis and preliminary evaluation of an 18F ‐labeled tubastatin A analog for PET imaging of histone deacetylase 6

Histone deacetylase 6 (HDAC6), a unique member of the HDAC family, has been implicated in cancers and neurodegenerative diseases. An18F ‐labeled analog of tubastatin A was synthesized for PET imaging of HDAC6, and a preliminary biological evaluation was performed. AbstractHistone 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 [18F]3, which is an analog of the HDAC6 ‐selective inhibitor tubastatin A, for positron emission tomography (PET) imaging. [18F]3 was synthesized by a two ‐step reaction composed of18F ‐fluorination and formation of a hydroxamic acid group. IC50 values of3 against HDAC1 and HDAC6 activities were 996 nM and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [18F]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 minutes post injection in mouse plasma. A small animal PET study in mice showed that pretreatment with cyclosporine A had no effect on initial brain uptake of [18F]3, suggesting low brain uptake of [18F]3 was not caused by the P ‐glycoprotein–mediated e...
Source: Journal of Labelled Compounds and Radiopharmaceuticals - Category: Biochemistry Authors: Tags: RESEARCH ARTICLE Source Type: research