Novel Potent Proline-Based Metalloproteinase Inhibitors: Design, (Radio)Synthesis, and First in Vivo Evaluation as Radiotracers for Positron Emission Tomography

As dysregulation
of matrix metalloproteinase (MMP) activity is
associated with a wide range of pathophysiological processes like
cancer, atherosclerosis, and arthritis, MMPs represent a valuable
target for the development of new therapeutics and diagnostic tools.
We herein present the chiral pool syntheses, in vitro evaluation,
and SAR studies of a series of d- and l-proline-
as well as of (4R)-4-hydroxy-l-proline-derived
MMP inhibitors possessing general formula 1. Some of
the synthesized hydroxamic acids were found to be potent MMP inhibitors
with IC50 values in the nanomolar range, also demonstrating
no off-target effects toward the other tested Zn2+-dependent
metalloproteases (ADAMs and meprins). Utilizing the structure of the
(2S,4S)-configured 4-hydroxyproline
derivative 4, a selective picomolar inhibitor of MMP-13,
the radiolabeled counterpart [18F]4 was successfully
synthesized. The radiotracer’s biodistribution in mice as well
as its serum stability were evaluated for assessing its potential
use as a MMP-13 targeting PET imaging agent.