Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging

Macrophage elastase [matrix metalloproteinase
(MMP)-12] is the
most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence,
MMP-12-targeted imaging may predict AAA progression and rupture risk.
Here, we report the design, synthesis, and evaluation of three novel
hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA)
and the methodology to obtain MMP-12 selectivity from hydroxamate-based
panMMP inhibitors. Also, we report two 99mTc-radiotracers, 99mTc-AGA-1 and 99mTc-AGA-2, derived from AGA. 99mTc-AGA-2 displayed faster blood clearance in mice and better
radiochemical stability compared to 99mTc-AGA-1. Based
on this, 99mTc-AGA-2 was chosen as the lead tracer and
tested in murine AAA. 99mTc-AGA-2 uptake detected by autoradiography
was significantly higher in AAA compared to normal aortic regions.
Specific binding of the tracer to MMP-12 was demonstrated through
ex vivo competition. Accordingly, this study introduces a novel family
of selective MMP-12 inhibitors and tracers, paving the way for further
development of these agents as therapeutic and imaging agents.