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.
Viktoria ButschFrederik BörgelFabian GallaKatrin SchwegmannSven HermannMichael SchäfersBurkhard RiemannBernhard WünschStefan WagnerPublished in: Journal of medicinal chemistry (2018)
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.
Keyphrases
- positron emission tomography
- computed tomography
- pet imaging
- chronic obstructive pulmonary disease
- cell migration
- pet ct
- high resolution
- cardiovascular disease
- lung function
- traumatic brain injury
- rheumatoid arthritis
- young adults
- papillary thyroid
- cystic fibrosis
- molecular dynamics simulations
- lps induced
- air pollution
- human health
- climate change
- molecular docking
- case control