title: A new generation of radiofluorinated pyrimidine-2,4,6-triones as MMP-targeted radiotracers for positron emission tomography.
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.
authors: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany.
authors: Daniela
authors: D
authors: Schrigten
authors: Hans-Jörg
authors: HJ
authors: Breyholz
authors: Stefan
authors: S
authors: Wagner
authors: Sven
authors: S
authors: Hermann
authors: Otmar
authors: O
authors: Schober
authors: Michael
authors: M
authors: Schäfers
authors: Günter
authors: G
authors: Haufe
authors: Klaus
authors: K
authors: Kopka
mesh_terms: D000818:Animals; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D005462:Fluorine Radioisotopes; D061965:Matrix Metalloproteinase Inhibitors; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D014230:Triazoles; D011092:Polyethylene Glycols; D020782:Matrix Metalloproteinases