Hypoxic tissue

Since the beginning of the 1990s, much effort has been devoted to develop J c radiopharmaceuticals for the detection of hypoxic tissue in the myocardium, brain. 

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A typical 19F NMR spectrum of a compound with a trifluorovinyl group is given in Fig. 6.20. This compound is the chemical precursor of the drug known as EF5, which is used in positron emission tomography imaging to detect hypoxic tissue. 

F-fluoromisonidazole [81] in hypoxic tissue have led to the development of such an agent based on 99mTc, All of these studies to date have involved the incorporation of the 2-nitroimidazole function onto a known stable complex for technetium. 

The accumulation of adenosine in hypoxic tissues can also be explained by the hypoxia-mediated upregulation of 5 -nucleotidase activity, an enzyme that converts AMP to adenosine, which results in the accumulation of extracellular adenosine... 

The resistance of many human cancers to immunotherapies has been attributed to the presence of immunosuppressive molecules located in tumor areas. Adenosine is present at elevated levels in hypoxic tissues due to an increased intracellular production and extracellular accumulation, as described above. This nucleoside activates cell surface receptors on T and NK cells that mediate cellular immune responses to tumor cells. It is well established that T cells recognize and destroy... 

The importance of the unrestricted availability of molecular oxygen at the site of and throughout, the photodynamic process will be clear from earlier discussion on the formation of Cy. Namely hypoxic tissue may not provide sufficient oxygen for the photodynamic process to occur. In an environment of limited oxygen availability, longer light exposure at lower intensity may provide an effective photodynamic effect, provided that the yield of102 exceeds the tissue s ability to quench. 

Recently, Gonzalez et al. described the synthesis and evaluation as hypoxic selective cytotoxins of a series of PDO and its reduced analogues, Pz, as the generated metabolic products into the hypoxic tissues [54]. Com-... 

I8F]-Fmiso, 50, needed for routine detection of hypoxic tissue in ischemic heart and brain, and tumours with PET71 has been obtained72 in rapid and high yield (80%, TLC, HPLC) radiosynthesis procedure of equation 32, similar to the preparation of [I8F]FDG73. The di-toluenesulphonate 51 has been prepared in four steps (13.5% overall yield) from readily available and inexpensive materials. 

Jaffar, M. and Stratford, I.J. (1999) Bioreductive drugs selectivity towards hypoxic tissues. Exp. Opin. Ther. Patents, 9 1371-1380. 

A second major clinical application for lidocaine and related sodium channel blockers consists in the suppression of arrhythmias in the heart, which most commonly arise there as a consequence of some hypoxic tissue damage. To understand this usage, we will briefly look at some details of heart physiology. 

Recent ""Tc-based imaging agents, shown in Figure 5, for hypoxic tissue are in development. These include nitroimidazole derivatives, BSM-181321 and BRU-59-2, based on the "Tc-propyleneamine oxime (PNAO) complexes. Both contain the 2-nitrounidazole functionality, that is the active component of the oxygen mimetic molecule, F-2-nitroimidazole, and have been shown in vivo to localize in ischemic tissue. The BnAO chelate also displays uptake in hypoxic tissue. The mechanism is unknown, however, electrochemical studies show an irreversible reduction at biologically accessible potentials. 

The thiosemicarbazone complexes CuPTSM and CuA-TSM, Fig. , have been used to image perfusion and hypoxia, respectively (36). It is believed that these compounds freely diffuse into cells. Reduction from Cu(II) to Cu(I) inside the cell causes the complex to faU apart, and the copper is trapped inside the ceU. The redox potential of CuATSM is lower than that of CuPTSM, and this redox potential is believed to be the root of the selectivity of CuATSM for hypoxic tissue. 

AQ4N (23) is a prodrug of the DNA binding agent and topoisomerase inhibitor AQ4 (23a). The less toxic prodrug is activated in hypoxic tissue through reduction of the iV-oxide (Scheme ll).46,47... 

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