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

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† Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States
§ Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, New York 10016, United States
∥ Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States
*(H.-Y.W.) Mailing address: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129. E-mail: [email protected]
*(J.M.H.) Mailing address: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129 E-mail: [email protected]. Telephone: 617-726-6596. Fax: 617-726-7422.
Cite this: ACS Chem. Neurosci. 2015, 6, 5, 708–715
Publication Date (Web):March 13, 2015
https://doi.org/10.1021/acschemneuro.5b00066
Copyright © 2015 American Chemical Society
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    Abstract

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    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 [11C]Martinostat, which exhibits selectivity for a subset of class I/IIb HDAC enzymes. In this study, we characterize the kinetic properties of [11C]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. [11C]Martinostat showed high baseline distribution volume (VT) ranging from 29.9 to 54.4 mL/cm3 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/cm3 suggests high specific binding of [11C]Martinostat. From a two-tissue compartment model, [11C]Martinostat exhibits a high K1 (averaged K1 of 0.65 mL/cm3/min) and a small k4 (average of 0.0085 min–1). Our study supports that [11C]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.

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