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A new generation of radiofluorinated pyrimidine-2,4,6-triones as MMP-targeted radiotracers for positron emission tomography.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 Jan 12; Vol. 55 (1), pp. 223-32. Date of Electronic Publication: 2011 Dec 13. - Publication Year :
- 2012
-
Abstract
- Radiolabeled C-5-disubstituted pyrimidine-2,4,6-triones have recently been suggested by our group as a class of potent matrix metalloproteinase (MMP) targeted radiotracers that can noninvasively visualize activated MMPs by means of positron emission tomography (PET). MMPs belong to the zinc- and calcium-dependent endopeptidases which are involved in the proteolytic degradation of components of the extracellular matrix (ECM) but also are capable of processing and releasing bioactive molecules such as growth factors, proteinase inhibitors, and cytokines. Locally increased levels of activated MMPs modulate and contribute to the progression of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific and noninvasive visualization of aforementioned pathologies in vivo. On the basis of our recent results, we here describe a series of new fluorinated pyrimidine-2,4,6-triones of the second generation with maintained MMP inhibition potencies (IC(50) = 4-605 nM), which are fine-tuned toward more hydrophilic versions, and show the improved biodistribution behavior of one selected radiofluorinated pyrimidine-2,4,6-trione by means of small-animal PET.
- Subjects :
- Animals
Drug Stability
Fluorine Radioisotopes
Humans
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases chemistry
Mice
Mice, Inbred BALB C
Polyethylene Glycols chemistry
Positron-Emission Tomography
Pyrimidines chemistry
Pyrimidines pharmacokinetics
Radiopharmaceuticals chemistry
Radiopharmaceuticals pharmacokinetics
Structure-Activity Relationship
Tissue Distribution
Triazoles chemical synthesis
Triazoles chemistry
Triazoles pharmacology
Matrix Metalloproteinases metabolism
Pyrimidines chemical synthesis
Radiopharmaceuticals chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22118188
- Full Text :
- https://doi.org/10.1021/jm201142w