Activity-related changes in brain HDAC with [F-18]FAHA PET in rats and monkeys

Objectives 6-([F-18]-fluoroacetamide)-1-hexanoicanilide ([F-18]FAHA), an analog of suberoylanilide hydroxamic acid (SAHA), is known as a novel PET probe of histone deacetylase (HDAC). In order to study the functional role of HDAC in the central nerve system, we try to perform the in vivo brain imaging of PET with [F-18]FAHA in rats and monkeys under the conscious and anesthetized states.

Methods [F-18]FAHA was synthesized according to the methods developed in our group in high specific activity (>2 Ci/µM). Brain dynamic PET-imaging with [F-18]FAHA was performed for 60 min in rats (Wistar, 8 weeks of age) and monkeys (Macaca mulatta, 6 years of age). Brain HDAC activity measured by PET under conscious condition using the unique method we have developed was compared with that under the condition of propofol and ketamine anesthesia. We also conducted [F-18]FDG PET imaging to monitor brain activity as reference.

Results [F-18]FAHA specifically accumulated in the rat brain by blocking [18F]FAHA uptake using SAHA. We here examined the influence of consciousness level on HDAC activity in brain measured by PET with [18F]FAHA. By propofol or ketamine anesthesia, standardized uptake values (SUVs) of [18F]FAHA were 20-30% higher than that under conscious condition, especially in the frontal cortical regions under ketamine anesthesia, while SUVs of [18F]FDG in the brain were decreased compared with that under conscious condition.

Conclusions [F-18]FAHA PET suggested the neural activity related changes in the HDAC activity of the brain in rats and monkeys. HDAC activity may play important roles in brain development and regional functions in both rodents and primates. PET imaging of HDAC activity is expected as a cue to the neural mechanisms of developmental psychiatric disorders