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 [¹¹¹In]-DTPA-RP782, [99mTc]-(HYNIC-RP805)(tricine)(TPPTS), or Marimastat-ArB[¹⁸F]F₃ and the picolyl- benzenesulfonamide [¹²³I]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.
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'-[ (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-term accumulation in organs and the possibility to accumulate in the tumor. These results warrant further studies of radioiodinated carboxylic and hydroxamic MMP inhibitor tracers as potential SPECT tumor imaging agents.
In this review, data on noninvasive imaging of apoptosis in oncology are reviewed. Imaging data available are presented in order of occurrence in time of enzymatic and morphologic events occurring during apoptosis. Available studies suggest that various radiopharmaceutical probes bear great potential for apoptosis imaging by means of positron emission tomography and single-photon emission computed tomography (SPECT). However, for several of these probes, thorough toxicologic studies are required before they can be applied in clinical studies. Both preclinical and clinical studies support the notion that 99mTc-hydrazinonicotinamide-annexin A5 and SPECT allow for noninvasive, repetitive, quantitative apoptosis imaging and for assessing tumor response as early as 24 hours following treatment instigation. Bioluminescence imaging and near-infrared fluorescence imaging have shown great potential in small-animal imaging, but their usefulness for in vivo imaging in humans is limited to structures superficially located in the human body. Although preclinical tumor-based data using high-frequency-ultrasonography (US) are promising, whether or not US will become a routinely clinically useful tool in the assessment of therapy response in oncology remains to be proven. The potential of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) for imaging late apoptotic processes is currently unclear. Neither 31P MRS nor 1H MRS signals seems to be a unique identifier for apoptosis. Although MRI-measured apparent diffusion coefficients are altered in response to therapies that induce apoptosis, they are also altered by nonapoptotic cell death, including necrosis and mitotic catastrophe. In the future, rapid progress in the field of apoptosis imaging in oncology is expected.
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