Background

[PubMed]

Extracellular matrix (ECM) adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). Invasive tumor cells adhere to the ECM, which provides a matrix environment for permeation of tumor cells through the basal lamina and underlying interstitial stroma of the connective tissue. Overexpression of matrix metalloproteinases (MMPs) and other proteases by tumor cells allows intravasation of tumor cells into the circulatory system after degrading the basement membrane and ECM (3).

Several families of proteases are involved in atherogenesis, inflammation, myocardial infraction, angiogenesis, and tumor invasion and metastasis (4-8). The gelatinase family is a subgroup of MMPs consisting of gelatinase A (MMP-2) and gelatinase B (MMP-9) (9). Gelatinase expression in normal cells, such as trophoblasts, osteoclasts, neutrophils, and macrophages, is highly regulated. Elevated levels of gelatinases have been found in tumors that are associated with a poor prognosis for cancer patients (10). A number of synthetic MMP inhibitors have been developed to block the activated MMPs in pathological conditions (11). (R)-2-(N-Benzyl-4-(2-fluoroethoxy)phenylsulfonamido)-N-hydroxy-3-methylbutanamide (1f) was found to be a potent MMP inhibitor (12). ¹⁸F-Labeled 1f ([¹⁸F]1f) is being developed for PET imaging of MMP proteolytic activity in tumors, atherosclerosis, myocardial infarction, and other diseases.

Synthesis

[PubMed]

[¹⁸F]1f was prepared as described by Wagner et al. (12). [¹⁸F]KF/Kryptofix 2.2.2/K₂CO₃ and the tosylate precursor, (R)-2-(N-benzyl-4-(2-(tosyloxy)ethoxy)phenylsulfonamido)-N-hydroxy-3-methylbutanamide, were heated in acetonitrile at 84°C for 4 min, followed by acidic hydrolysis in trifluoroacetic acid and high-performance liquid chromatography (HPLC). Average radiochemical yield was 12.4 ± 3.0% (n = 5) with a total synthesis time of 113 ± 6 min. Radiochemical purity was >97% with specific activities of 44 ± 19 GBq/µmol (1.19 ± 0.51 Ci/µmol) at end of synthesis. [¹⁸F]1f has a log D_7.4 value of 2.02.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Wagner et al. (12) performed in vitro fluorogenic inhibition assays for MMP-2, MMP-8, MMP-9, and MMP-13. The MMP inhibitor 1f exhibited IC₅₀ values of 4 ± 3 nM for MMP-2, 2 ± 1 nM for MMP-8, 50 ± 27 nM for MMP-9, and 11 ± 0.3 nM for MMP-13.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

References

1.

Bosman F.T. , Stamenkovic I. Functional structure and composition of the extracellular matrix. J Pathol. 2003; 200 (4):423–8. [PubMed: 12845610]

2.

Jiang W.G. , Puntis M.C. , Hallett M.B. Molecular and cellular basis of cancer invasion and metastasis: implications for treatment. Br J Surg. 1994; 81 (11):1576–90. [PubMed: 7827878]

3.

Albelda S.M. Role of integrins and other cell adhesion molecules in tumor progression and metastasis. Lab Invest. 1993; 68 (1):4–17. [PubMed: 8423675]

4.

Keppler D. , Sameni M. , Moin K. , Mikkelsen T. , Diglio C.A. , Sloane B.F. Tumor progression and angiogenesis: cathepsin B & Co. Biochem Cell Biol. 1996; 74 (6):799–810. [PubMed: 9164649]

5.

Liu J. , Sukhova G.K. , Sun J.S. , Xu W.H. , Libby P. , Shi G.P. Lysosomal cysteine proteases in atherosclerosis. Arterioscler Thromb Vasc Biol. 2004; 24 (8):1359–66. [PubMed: 15178558]

6.

Berchem G. , Glondu M. , Gleizes M. , Brouillet J.P. , Vignon F. , Garcia M. , Liaudet-Coopman E. Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis. Oncogene. 2002; 21 (38):5951–5. [PubMed: 12185597]

7.

Brix K. , Dunkhorst A. , Mayer K. , Jordans S. and Cysteine cathepsins: Cellular roadmap to different functions. Biochimie. 2007 [PubMed: 17825974]

8.

Beaudeux J.L. , Giral P. , Bruckert E. , Foglietti M.J. , Chapman M.J. Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives. Clin Chem Lab Med. 2004; 42 (2):121–31. [PubMed: 15061349]

9.

Nelson A.R. , Fingleton B. , Rothenberg M.L. , Matrisian L.M. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000; 18 (5):1135–49. [PubMed: 10694567]

10.

Deryugina E.I. , Quigley J.P. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006; 25 (1):9–34. [PubMed: 16680569]

11.

Skiles J.W. , Gonnella N.C. , Jeng A.Y. The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors. Curr Med Chem. 2004; 11 (22):2911–77. [PubMed: 15544483]

12.

Wagner S. , Breyholz H.J. , Law M.P. , Faust A. , Holtke C. , Schroer S. , Haufe G. , Levkau B. , Schober O. , Schafers M. , Kopka K. Novel fluorinated derivatives of the broad-spectrum MMP inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)- and (3-picolyl)-amino]-3-methyl-butanamide as potential tools for the molecular imaging of activated MMPs with PET. J Med Chem. 2007; 50 (23):5752–64. [PubMed: 17956082]