cn5b00297_si_001.pdf (1.7 MB)
Development of a Fluorinated Class‑I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance
journal contribution
posted on 2015-12-16, 00:00 authored by Martin G. Strebl, Changning Wang, Frederick
A. Schroeder, Michael S. Placzek, Hsiao-Ying Wey, Genevieve
C. Van de Bittner, Ramesh Neelamegam, Jacob M. HookerDespite
major efforts, our knowledge about many brain diseases
remains remarkably limited. Epigenetic dysregulation has been one
of the few leads toward identifying the causes and potential treatments
of psychiatric disease over the past decade. A new positron emission
tomography radiotracer, [11C]Martinostat, has enabled the
study of histone deacetylase in living human subjects. A unique property
of [11C]Martinostat is its profound brain penetrance, a
feature that is challenging to engineer intentionally. In order to
understand determining factors for the high brain-uptake of Martinostat,
a series of compounds was evaluated in rodents and nonhuman primates.
The study revealed the major structural contributors to brain uptake,
as well as a more clinically relevant fluorinated HDAC radiotracer
with comparable behavior to Martinostat, yet longer half-life.