The 99mTc-EC platform enables many different ligands to be radiolabeled without resorting to new, highly complex radiochemistry each time a new ligand is introduced. Such a "reductionist" approach presupposes the development of automated synthesis chambers, which could allow the onsite radiolabeling of a wide range of ligands in a single radiopharmacy. The use of a ubiquitous isotope, a uniform chelation method along with imaging with conventional planar or SPECT imaging can dramatically lower study costs associated with molecular imaging. In this chapter,

Figure 25 No marked differences of cellular uptake of 99mTc-EC-Guan between viral tans-fection of HSV tk expression and without HSV tk expression.

Tc-EC-Guan Imaging In Rabbits

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Figure 26 Planar scintigraphy of 99mTc-EC-Guan in VX2 tumor-bearing rabbits (1mCi/ rabbit, IV) demonstrates that the tumor could be well visualized.

only a few of the many radioligands that can be produced by the 99mTc-EC-construct is discussed.

The 99mTc-EC-DG, for instance, could serve as a substitute for FDG-PET and thus, provide metabolic information about glycolysis and cell turnover. Angiogenesis imaging is another potentially important target for this technology. Imaging with radiolabeled antiangiogenic agents has the following potential advantages over biopsy: (i) noninvasive assessment, (ii) easily quantifiable, (iii) can be used to access anatomical regions that are difficult to biopsy, and (iv) whole body evaluations. Though histological assessments of angiogenesis (blood vessel density) and/or its main regulators such as IL-8, VEGF, and bFGF in solid tumors may provide sensitive markers for tumor progression, metastasis, and prognosis, the therapeutic response of tumors may not be adequately reflected by these histologic measurements. The role of 99mTc-EC-endostatin in imaging tumors that over-express endothelial markers associated with angiogenesis needs to be evaluated. The findings

MmTc-EC Imaging In Rabbits

MmTc-EC Imaging In Rabbits

Figure 27 Planar scintigraphy of 99mTc-EC in VX2 tumor-bearing rabbits (1 mCi/rabbit, IV) demonstrate that the tumor could be well visualized. Tumor versus nontumor ratios were 2.04 and 1.20.

Figure 27 Planar scintigraphy of 99mTc-EC in VX2 tumor-bearing rabbits (1 mCi/rabbit, IV) demonstrate that the tumor could be well visualized. Tumor versus nontumor ratios were 2.04 and 1.20.

suggest that the combination use of endostatin with cytotoxic chemotherapeutic agents or radiation therapy may enhance the efficiency of endostatin therapy. &132#However, radiolabeled endostatin was found to be useful as a biological response marker in assessing endostatin therapy. Scintigraphic images showed good visualization of the tumor, as well as a correlation between tumor uptake and treatment effects. Decreased tumor versus nontumor uptake of radiolabeled endostatin following endostatin or paclitaxel treatment correlated with decreased tumor volume at the end of treatment as well as decreased expression of angiogenic factors. In other words, the decrease in tumor uptake of 99mTc-EC-endostatin signified effective antitumor activity. For anti-EGFR antibody and COX-2 antagonist, in vitro and in vivo biodistribution studies demonstrated the feasibility of using 99mTc-EC-C225 and 99mTc-EC-celebrex to assess EGFR and cox-2 expression. EGFR is over expressed in a significant percentage of human A431 cells, which correlates well with 99mTc-EC-C225 uptake. Animal studies and preliminary clinical imaging studies suggest that 99mTc-EC-C225, a specific marker for EGFR, may be useful in selecting patients most likely to benefit from C225 therapy.

Tissue hypoxia is another important predictor of therapeutic response. There was a significantly increased tumor versus tissue uptake ratio as a function of time in the 99mTc-EC-MN group. When compared with [18F]FMISO and [131I]IMISO, the tumor versus tissue uptake ratios for 99mTc-EC-MN were similar to those of [131I]IMISO. Thyroid tissue uptake was not altered after 99mTc-EC-MN, whereas thyroid uptake increased with [131I] IMISO. The findings suggest that 99mTc-EC-MN is more metabolically stable than [131I] IMISO. Tumor oxygen tension was determined to be 3.2 to 6.0 mmHg within the hypoxic regions, whereas normal muscle tissue demonstrated oxygen tension readings of 30 to 40 mmHg. The findings support further studies to determine normal tissue dosimetry, measuring sensitizer enhancement ratio (SER) and identifying whether 99mTc-EC-MN can provide a rational means of selecting patients for treatment with radiosensitizing (e.g., SR-2508 and Ro-03-8799) or bioreductive agents.

Apoptosis occurs during treatment with chemotherapy and radiation (25,26,5962). Apoptosis can occur early, before tumor volume changes, and thus, is an early marker of treatment efficacy. Annexin V is known to bind phosphatidylserine, which is overexpressed by apoptotic cells as a signal for clearance by macrophages. Assessment of apoptosis by annexin V could be useful to evaluate the efficacy of therapy and disease progression or regression. Increased uptake of annexin V at earlier time points, and later decreased uptake after treatment would reflect a positive treatment response. Unfortunately, not all apoptotic cells express phosphatidylserine in their outer membrane. Thus, this agent could become a critical pathway common for the assessment of tumor treatment regimens as many of them eventually cause apoptosis.

Other agents such as 99mTc-EC-doxorubicin,99mTc-EC-LHRH, and 99mTc-EC-guanosine analog could be useful markers of MDR, sensitivity to hormone therapy, and proliferation markers. The diversity of radiolabeled biomarkers could lead to a more complete assessment of the biological characteristics of tumors.

In summary, EC-conjugates to Technetium can be used to synthesize radiolabeled targeted molecular imaging agents. The chemical synthesis of these agents lends itself to automation and the broad range of ligands that are "chelatable" means that this is a highly flexible and versatile system for radiolabeling. The use of technetium, which can be produced by a desktop generator at low cost, with good energy levels for external detection and a six hour half-life makes this radioisotope suitable for molecular imaging in man.

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