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A new class of highly potent matrix metalloproteinase inhibitors based on triazole-substituted hydroxamates: (radio)synthesis and in vitro and first in vivo evaluation.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 May 24; Vol. 55 (10), pp. 4714-27. Date of Electronic Publication: 2012 May 16. - Publication Year :
- 2012
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Abstract
- In vivo imaging of MMPs is of great (pre)clinical interest and can potentially be realized with modern three-dimensional and noninvasive in vivo molecular imaging techniques such as positron emission tomography (PET). Consequently, MMP inhibitors (MMPIs) radiolabeled with positron emitting nuclides (e.g., (18)F) represent a suitable tool for the visualization of activated MMPs with PET. On the basis of our previous work and results regarding radiolabeled and unlabeled derivatives of the nonselective MMPIs, we discovered a new class of fluorinated MMPIs with a triazole-substituted hydroxamate substructure. These novel MMPIs are characterized by an increased hydrophilicity compared with the lead structures and excellent MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13 (IC(50) = 0.006-107 nM). Therefore, one promising fluorinated triazole-substituted hydroxamate (30b) was selected and resynthesised as its (18)F-labeled version to yield the potential PET radioligand [(18)F]30b. The biodistribution behavior of this novel compound was investigated with small animal PET.
- Subjects :
- Animals
Drug Stability
Enzyme Assays
Fluorine Radioisotopes
Humans
Hydrophobic and Hydrophilic Interactions
Hydroxamic Acids chemistry
Hydroxamic Acids pharmacokinetics
Matrix Metalloproteinases chemistry
Mice
Mice, Inbred C57BL
Positron-Emission Tomography
Radiopharmaceuticals chemistry
Radiopharmaceuticals pharmacokinetics
Stereoisomerism
Structure-Activity Relationship
Sulfonamides chemistry
Sulfonamides pharmacokinetics
Tissue Distribution
Triazoles chemistry
Triazoles pharmacokinetics
Hydroxamic Acids chemical synthesis
Matrix Metalloproteinase Inhibitors
Radiopharmaceuticals chemical synthesis
Sulfonamides chemical synthesis
Triazoles chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22540974
- Full Text :
- https://doi.org/10.1021/jm300199g