2 research outputs found
Identification of [<sup>18</sup>F]TRACK, a Fluorine-18-Labeled Tropomyosin Receptor Kinase (Trk) Inhibitor for PET Imaging
Changes in expression and dysfunctional
signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins
are found in neurological diseases and cancers. Here, we describe
the development of a first <sup>18</sup>F-labeled optimized lead suitable
for in vivo imaging of Trk,
[<sup>18</sup>F]ÂTRACK, which is radiosynthesized with ease from a
nonactivated aryl precursor concurrently combining largely reduced
P-gp liability and improved brain kinetics compared to previous leads
while displaying high on-target affinity and human kinome selectivity
A Kinome-Wide Selective Radiolabeled TrkB/C Inhibitor for in Vitro and in Vivo Neuroimaging: Synthesis, Preclinical Evaluation, and First-in-Human
The
proto-oncogenes <i>NTRK1/2/3</i> encode the tropomyosin
receptor kinases TrkA/B/C which play pivotal roles in neurobiology
and cancer. We describe herein the discovery of [<sup>11</sup>C]-(<i>R</i>)-<b>3</b> ([<sup>11</sup>C]-(<i>R</i>)-IPMICF16),
a first-in-class positron emission tomography (PET) TrkB/C-targeting
radiolabeled kinase inhibitor lead. Relying on extensive human kinome
vetting, we show that (<i>R</i>)-<b>3</b> is the most
potent and most selective TrkB/C inhibitor characterized to date.
It is demonstrated that [<sup>11</sup>C]-(<i>R</i>)-<b>3</b> readily crosses the blood–brain barrier (BBB) in
rodents and selectively binds to TrkB/C receptors in vivo, as evidenced
by entrectinib blocking studies. Substantial TrkB/C-specific binding
in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimer’s disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [<sup>11</sup>C]-(<i>R</i>)-<b>3</b> in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human