Kinetic Analysis and Quantification of [¹¹C]Martinostat for in Vivo HDAC Imaging of the Brain

ACS Chem Neurosci. 2015 May 20;6(5):708-15. doi: 10.1021/acschemneuro.5b00066. Epub 2015 Mar 25.


Epigenetic mechanisms mediated by histone deacetylases (HDACs) have been implicated in a wide-range of CNS disorders and may offer new therapeutic opportunities. In vivo evaluation of HDAC density and drug occupancy has become possible with [(11)C]Martinostat, which exhibits selectivity for a subset of class I/IIb HDAC enzymes. In this study, we characterize the kinetic properties of [(11)C]Martinostat in the nonhuman primate (NHP) brain in preparation for human neuroimaging studies. The goal of this work was to determine whether classic compartmental analysis techniques were appropriate and to further determine if arterial plasma is required for future NHP studies. Using an arterial plasma input function, several analysis approaches were evaluated for robust outcome measurements. [(11)C]Martinostat showed high baseline distribution volume (VT) ranging from 29.9 to 54.4 mL/cm(3) in the brain and large changes in occupancy (up to 99%) with a blocking dose approaching full enzyme saturation. An averaged nondisplaceable tissue uptake (VND) of 8.6 ± 3.7 mL/cm(3) suggests high specific binding of [(11)C]Martinostat. From a two-tissue compartment model, [(11)C]Martinostat exhibits a high K1 (averaged K1 of 0.65 mL/cm(3)/min) and a small k4 (average of 0.0085 min(-1)). Our study supports that [(11)C]Martinostat can be used to detect changes in HDAC density and occupancy in vivo and that simplified analysis not using arterial blood could be appropriate.

Keywords: Epigenetic regulation; PET; histone deacetylases; kinetic model; occupancy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacokinetics
  • Animals
  • Brain / diagnostic imaging*
  • Carbon Radioisotopes / pharmacokinetics
  • Female
  • Histone Deacetylases / metabolism*
  • Hydroxamic Acids / pharmacokinetics*
  • Image Processing, Computer-Assisted
  • Male
  • Papio
  • Positron-Emission Tomography / methods*
  • Radiopharmaceuticals / pharmacokinetics*


  • Carbon Radioisotopes
  • Hydroxamic Acids
  • Radiopharmaceuticals
  • martinostat
  • Histone Deacetylases
  • Adamantane