Design, (Radio)Synthesis, and in Vitro and in Vivo Evaluation of Highly Selective and Potent Matrix Metalloproteinase 12 (MMP-12) Inhibitors as Radiotracers for Positron Emission Tomography

Dysregulated
levels of activated matrix metalloproteinases (MMPs)
are linked to different pathologies, such as cancer, atherosclerosis,
neuroinflammation, and arthritis. Therefore, imaging of MMPs with
positron-emission tomography (PET) represents a powerful tool for
the diagnosis of MMP-associated diseases. Moreover, to distinguish
between the distinct functions and roles of individual MMPs in particular
pathophysiological processes, their specific imaging must be realized
with radiolabeled tracers, such as fluorine-18-labeled MMP inhibitors
(MMPIs). Therefore, fluorinated dibenzofuransulfonamide-based MMPIs
showing excellent inhibition of MMP-12 and selectivity for MMP-12
over other MMPs were prepared. MMP-12 is a key enzyme in diseases
such as chronic obstructive pulmonary disease (COPD) and atherosclerosis.
Because of their promising in vitro properties, three candidates (4, 9, and 19) were selected from
this library, and radiofluorinated analogues ([18F]­4, [18F]­9, and [18F]­19) were successfully synthesized. Initial in vitro
serum stability and in vivo biodistribution studies of the radiolabeled
MMPIs with PET demonstrated their potential benefit for preferable
MMP-12 imaging.