title: C-5-disubstituted barbiturates as potential molecular probes for noninvasive matrix metalloproteinase imaging.
abstract: 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.
authors.affiliation: Department of Nuclear Medicine, University Hospital of the Westfälische Wilhelms-Universität, Münster, Germany. breyholz@uni-muenster.de
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Breyholz
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Carsten
authors.initials: C
authors.lastname: Höltke
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.forename: Helmut
authors.initials: H
authors.lastname: Rabeneck
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
mesh_terms: 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
chemical_list: 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