Evaluation of 6-([(18)F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain.

Abstract:

INTRODUCTION:Histone deacetylases (HDACs) are enzymes involved in epigenetic modifications that shift the balance toward chromatin condensation and silencing of gene expression. Here, we evaluate the utility of 6-([(18)F]fluoroacetamido)-1-hexanoicanilide ([(18)F]FAHA) for positron emission tomography imaging of HDAC activity in the baboon brain. For this purpose, we assessed its in vivo biodistribution, sensitivity to HDAC inhibition, metabolic stability and the distribution of the putative metabolite [(18)F]fluoroacetate ([(18)F]FAC). METHODS:[(18)F]FAHA and its metabolite [(18)F]FAC were prepared, and their in vivo biodistribution and pharmacokinetics were determined in baboons. [(18)F]FAHA metabolism and its sensitivity to HDAC inhibition using suberanilohydroxamic acid (SAHA) were assessed in arterial plasma and by in vitro incubation studies. The chemical form of F-18 in rodent brain was assessed by ex vivo studies. Distribution volumes for [(18)F]FAHA in the brain were derived. RESULTS:[(18)F]FAHA was rapidly metabolized to [(18)F]FAC, and both labeled compounds entered the brain. [(18)F]FAHA exhibited regional differences in brain uptake and kinetics. In contrast, [(18)F]FAC showed little variation in regional brain uptake and kinetics. A kinetic analysis that takes into account the uptake of peripherally produced [(18)F]FAC indicated that SAHA inhibited binding of [(18)F]FAHA in the baboon brain dose-dependently. In vitro studies demonstrated SAHA-sensitive metabolism of [(18)F]FAHA to [(18)F]FAC within the cell and diffusion of [(18)F]FAC out of the cell. All radioactivity in brain homogenate from rodents was [(18)F]FAC at 7 min postinjection of [(18)F]FAHA. CONCLUSION:The rapid metabolism of [(18)F]FAHA to [(18)F]FAC in the periphery complicates the quantitative analysis of HDAC in the brain. However, dose-dependent blocking studies with SAHA and kinetic modeling indicated that a specific interaction of [(18)F]FAHA in the brain was observed. Validating the nature of this interaction as HDAC specific will require additional studies.

journal_name

Nucl Med Biol

authors

Reid AE,Hooker J,Shumay E,Logan J,Shea C,Kim SW,Collins S,Xu Y,Volkow N,Fowler JS

doi

10.1016/j.nucmedbio.2008.12.005

subject

Has Abstract

pub_date

2009-04-01 00:00:00

pages

247-58

issue

3

eissn

0969-8051

issn

1872-9614

pii

S0969-8051(08)00253-9

journal_volume

36

pub_type

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