Probes for Non-invasive Matrix Metalloproteinase-targeted Imaging with PET and SPECT

Dysregulation of matrix metalloproteinase (MMP) activity can lead to a wide range of disease states such as atherosclerosis, inflammation or cancer. The ability to image MMP activity non-invasively in vivo, by radiolabelled synthetic inhibitors, would allow the characterization of atherosclerotic plaques, inflammatory lesions or tumors. Here we present an overview of radiolabelled MMP inhibitors (MMPIs) and MMP peptides for positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the detection of proteolytic activity of MMPs. So far, most studies are at a preliminary stage; however, some hydroxamate-based tracers such as the peptidomimetics [In-111]-DTPA-RP782, [Tc-99m]-(HYNIC-RP805)(tricine)(TPPTS), or Marimastat-ArB[F-18]F-3 and the picolyl-benzenesulfonamide [I-123]I-HO-CGS 27023A identified specifically the enzymatic action of MMPs in animal models of various pathologies. The development of new compounds that may lead to novel tracers (e.g. modification of zinc-binding group, variation of substituents attached to the S1', S2' and S3' pockets of the MMP inhibitors) and the use of antibodies and cell penetrating peptides are also discussed. In general, preclinical studies with atherosclerosis models proved to be more successful than those with oncological models

Imaging probes targeting matrix metalloproteinases

During the past few years, several imaging probes targeting matrix metalloproteinases (MMPs) have been developed. Most of these probes have been validated in animal models. Overall, results derived from most of these studies have been disappointing. Whether or not this relates to shortcomings of the imaging probes used or to the set-up of the reported studies is currently unclear. Firstly, MMPs targeted in these studies, MMP-1, -2 and -9, are cell secreted and their expression is known to vary extensively within one tumor type, depending on the stage of development of the tumor and on the presence of naturally occurring TIMPs. Given the lack of data on the levels of MMP expression by incoculated tumor tissue at the time of imaging in most studies reported, it cannot be excluded that the negative results reported are, in fact, false-negative imaging results. Secondly, given that most of the agents used for imaging are intrinsically broad-spectrum agents, their higher affinity for specific subsets of MMPs does not necessarily imply that a positive imaging result also corresponds to overexpression of specific subsets of MMPs, as suggested in some papers published. Accordingly, well-characterized tumor models need to be developed for the purpose of validating currently available, as well as future, MMP-imaging probes. So far, only In-111-DTPA-N-TIMP-2 has been injected in patients, respectively suffering from Kaposi Sarcoma. Imaging results obtained with this agent proved disappointing. Imaging results obtained with other MMP-targeting probes in patients are awaited

Fluorescentie van de celviabiliteit na weefseltransplantatie : literatuuronderzoek /

Diss. 2de proef apotheke

Valine-based biphenylsulphonamide matrix metalloproteinase inhibitors as tumor imaging agents

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

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

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