C-5-disubstituted barbiturates as potential molecular probes for noninvasive matrix metalloproteinase imaging.
Studies have demonstrated a positive correlation between inflammation, metastasis, or atherosclerosis and the unbalanced or culminated expression of matrix metalloproteinases (MMPs). The molecular imaging of locally upregulated MMP activity in vivo is a clinical challenge. Actually, radioligands based on nonpeptidyl MMP inhibitors (MMPIs) are currently in development as putative radiopharmaceutical agents for the noninvasive in vivo assessment of activated MMPs. Nonpeptidyl MMPIs bind to the zinc active site of the activated enzyme via mono- (e.g. carboxylate) or bidentate (e.g. hydroxamate) complexation thereby exhibiting a broad-spectrum MMP binding potency. Thus, these mentioned endopeptidase inhibitors should be useable lead compounds for the redevelopment as diagnostic MMPI radiotracers. Recently, the non-hydroxamate C-5-disubstituted pyrimidine-2,4,6-triones were disclosed as subgroup-selective MMP inhibitors. We here describe a set of fine-tuned barbiturates as a new class of MMPI radiotracers for the noninvasive in vivo visualization of activated MMPs using scintigraphic techniques such as SPECT or PET.
Breyholz
Hans-Jörg
HJ
Department of Nuclear Medicine, University Hospital of the Westfälische Wilhelms-Universität, Münster, Germany. breyholz@uni-muenster.de
Schäfers
Michael
M
Wagner
Stefan
S
Höltke
Carsten
C
Faust
Andreas
A
Rabeneck
Helmut
H
Levkau
Bodo
B
Schober
Otmar
O
Kopka
Klaus
K
D001463:Barbiturates / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D020782:Matrix Metalloproteinases / Q000737:chemistry*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D049268:Positron-Emission Tomography; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon
C500854:5-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(4-(4-iodophenoxy)phenyl)pyrimidine-2,4,6-trione; D001463:Barbiturates; D007457:Iodine Radioisotopes; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9