Valine-based biphenylsulphonamide matrix metalloproteinase inhibitors as tumor imaging agents.

Abstract

Among matrix metalloproteinases (MMPs), the subfamily of gelatinases (MMP-2, MMP-9) is of particular interest due to their ability to degrade type IV collagen and other non-fibrillar collagen domains and proteins such as fibronectin and laminin. Whilst malignant cells often over-express various MMPs, the gelatinases have been most consistently detected in malignant tissues and associated with tumor growth, metastatic potential and angiogenesis. Radiosynthesis of carboxylic (1') and hydroxamic (2') MMPIs resulted in radiochemical yields of 70 +/- 5% (n = 6) and 60 +/- 5% (n = 4), respectively. Evaluation in A549-inoculated athymic mice showed a tumor uptake of 2. 0+/- 0.7%ID/g (3 h p.i.), a tumor/blood ratio of 0.5 and a tumor/muscle ratio of 4.6 at 48 h p.i. for 1'. For compound 2' a tumor uptake of 0.7 +/- 0.2%ID/g (3 h p.i.), a tumor/blood ratio of 1.2 and a tumor/muscle ratio of 1.8 at 24 h p.i. were observed. HPLC analysis of the blood (plasma) showed no dehalogenation or other metabolites of 1' 2 h p.i. For compound 2', 65.4% of intact compound was found in the blood (plasma) and one polar metabolite (31%) was detected whereas in the tumor 91.8% of the accumulated activity was caused by intact compound and only 8.1% by the metabolite. Planar imaging, using a Toshiba GCA-9300A/hg SPECT camera, showed that tumor tissue could be visualized and that image quality improved by decreasing specific activity resulting in lower liver uptake, indicating some degree of saturable binding in the liver. In vivo evaluation of these radioiodinated carboxylic and hydroxamic MMP inhibitor tracers revealed that MMP inhibitors could have potential as tumor imaging agents, but that further research is necessary.

• Authors: Ruth Oltenfreiter, Ludovicus Staelens, Veerle Kersemans, Bart Cornelissen, Francis Frankenne, Jean-Michel Foidart, Christophe Van de Wiele, Guido Slegers
• Journal: Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine (Appl Radiat Isot) Vol. 64 Issue 6 Pg. 677-85 (Jun 2006) ISSN: 0969-8043 [Print] England
• PMID: 16546398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(4'-iodobiphenyl-4-sulfonylamino)-3-methylbutyramide
• 2-(4'-iodobiphenyl-4-sulfonylamino)-3-methylbutyric acid
• Biphenyl Compounds
• Butyrates
• Iodine Radioisotopes
• Matrix Metalloproteinase Inhibitors
• Radiopharmaceuticals
• Serum Albumin
• Sulfonamides
• Valine

Topics

• Animals
• Biphenyl Compounds
• Butyrates (chemical synthesis, pharmacology)
• Iodine Radioisotopes
• Male
• Matrix Metalloproteinase Inhibitors
• Mice
• Mice, Nude
• Neoplasms, Experimental (diagnostic imaging, metabolism)
• Organ Specificity
• Radiopharmaceuticals (chemical synthesis, pharmacokinetics)
• Serum Albumin
• Sulfonamides (chemical synthesis, pharmacology)
• Tomography, Emission-Computed, Single-Photon
• Valine (chemistry)