Valine-based biphenylsulphonamide matrix metalloproteinase inhibitors as tumor imaging agents

in Applied Radiation & Isotopes (2006), 64(6), 677-685

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 ... [more ▼]

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. (c) 2006 Elsevier Ltd. All rights reserved. [less ▲]

Synthesis, quality control and in vivo evaluation of [I-123] rhTIMP-2, a potential tumour-imaging agent

in Journal of Labelled Compounds & Radiopharmaceuticals (2005), 48(5), 387-396

Matrix metalloproteinases (MMPs) are enzymes involved in the turnover of the extracellular matrix. Their overexpression in tumours may provide a target for diagnostic imaging by using labelled MMP ... [more ▼]

Matrix metalloproteinases (MMPs) are enzymes involved in the turnover of the extracellular matrix. Their overexpression in tumours may provide a target for diagnostic imaging by using labelled MMP inhibitors. MMPs are inhibited by endogenous tissue inhibitors of metalloproteinases (TIMPs). The enhanced production of MT1-MMP, located on the surface of cells within or in the direct vicinity of the tumour, and the high affinity interaction between TIMP-2 and MT1-MMP suggested that TIMP-2 could be a potential agent for non-invasive monitoring of cancer MMP levels, diagnosis of primary and secondary tumours and tumour response to MMP inhibitor therapy. There is also evidence that I-125-rhTIMP-2 internalizes, which is an important feature for its possible use as a radiotherapeuticum if labelled with I-131. Labelling of rhTIMP-2 was performed using the iodogen method resulting in a radiochemical yield of 51.1 +/- 11.8% (n = 5) and a radiochemical purity of > 98%. The trichloroacetic acid (TCA) precipitability of I-123 rhTIMP-2 was 95.2%. SDS-PAGE confirmed the correct size (21 kDa) of the purified I-123 rhTIMP-2 without degradation. HPLC showed one radioactive peak with a retention time corresponding to the nonlabelled rhTIMP-2. In vivo biodistribution showed no long-term accumulation in organs and the possibility to accumulate in the tumour. These results show the potential of I-123 rhTIMP-2 as tumour-imaging agent. Copyright (c) 2005 John Wiley [less ▲]

Tryptophane-based biphenylsulfonamide matrix metalloproteinase inhibitors as tumor imaging agents

in Cancer Biotherapy & Radiopharmaceuticals (2005), 20(6), 639-47

Aim: As a part of our efforts to use small organic matrix metalloproteinase (MMP) inhibitors with improved characteristics for the diagnosis and treatment of different kinds of tumor tissues ... [more ▼]

Aim: As a part of our efforts to use small organic matrix metalloproteinase (MMP) inhibitors with improved characteristics for the diagnosis and treatment of different kinds of tumor tissues, biphenylsulfonamide analogues were synthesized. This study reports on the in vivo biodistribution of iodine-123-labeled biphenylsulfonide and analogues in A549 lung carcinoma inoculated into athymic mice and the evaluation of their suitability as imaging agents using a single photon emission computed tomography (SPECT) camera. Methods: The radioiodinated carboxylic and hydroxamic MMP inhibitors 2-(4′- [123I]iodobiphenyl-4-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid (1′) and 2-(4′-[123I]iodobiphenyl-4- sulfonylamino)-3-(1H-indol-3-yl)-propionamide (2′) were synthesized by electrophilic aromatic substitution of the tributylstannyl derivatives. Planar gamma camera imaging was performed in nu/nu athymic mice bearing an A549 tumor using a Toshiba GCA-9300A/hg SPECT camera in planar mode equipped with a high-resolution, parallel-hole collimator. Results: Radiosynthesis of (1′) and (2′) resulted in radiochemical yields of 60 ± 5% (n ± 3) and 70 ± 5% (n = 6), respectively. Evaluation of tumors induced in athymic mice by the inoculation of non-small cell lung A549 carcinoma cells, showed a tumor uptake of 0.27–0.01 percent injected dose per gram (%ID/g) (3 hours–48 hours p.i.), a tumor-blood ratio of 0.7, a tumor-muscle ratio of 1.6, and a tumor-fat ratio of 0.5 at 24 hours (p.i.) for compound 1′. For compound 2′ a tumor uptake of 0.7–0.04 %ID/g (3 hours–48 hours p.i.), a postinjection tumor-blood ratio of 1.2, a tumor-muscle ratio of 3.2, and a tumor-fat ratio of 2.4 at 48 hours p.i. was observed. SPECT evaluation confirmed the results obtained from biodistribution. Conclusion: In vivo evaluation of these radioiodinated carboxylic and hydroxamic MMP inhibitor tracers revealed that they do not appear suitable as tumor-imaging agents. [less ▲]

New radioiodinated carboxylic and hydroxamic matrix metalloproteinase inhibitor tracers as potential tumor imaging agents

in Nuclear Medicine & Biology (2004), 31(4), 459-468

Several studies have demonstrated a positive correlation between tumor progression and expression of extracellular proteinases such as matrix metalloproteinases (MMPs). MMP-2 and MMP-9 have become ... [more ▼]

Several studies have demonstrated a positive correlation between tumor progression and expression of extracellular proteinases such as matrix metalloproteinases (MMPs). MMP-2 and MMP-9 have become attractive targets for cancer research because of their increased expression in human malignant tumor tissues of various organs, providing a target for medical imaging techniques. Radioiodinated carboxylic and hydroxamic MMP inhibitors 2-(4'-[123]iodo-biphenyl-4-sulfonylainino)-3-(1H-indol-3-yl)-propionic acid (9) and 2-(4'-[I-123] iodo-biphenyl-4-sulfonylamino)-3-(1H-indol-3-yl)-propionamide (11) were synthesized by electrophilic aromatic substitution of the tributylstannyl derivatives and resulted in radiochemical yields of 60% +/- 5% (n - 3) and 70% +/- 5% (n = 6), respectively. In vitro zymography and enzyme assays showed high inhibition capacities of the inhibitors on gelatinases. In vivo biodistribution showed no long-terin accumulation in organs and the possibility to accumulate in the tumor. These results warrant further studies of radioiodinated carboxylic and hydroxamic MNIP inhibitor tracers as potential SPECT tumor imaging agents. (C) 2004 Elsevier Inc. All rights reserved. [less ▲]