We propose a series of animal studies to assess the potential diagnostic value of imaging human brain tumors using two nonmetabolized [1-11C]- labeled amino acids, 1-aminocyclopentane carboxyylic acid (ACPC) and a- aminoisobutyric acid (AIB), and positron emission tomography (PET). Our hypotheses are that ACPC and AIB are """"""""better"""""""" imaging agents than [18F]- fluoro-2-deoxy-D-glucose (FDG) or [11C]-methionine, and that ACPC and AIB imaging will provide clinically useful information which can not be obtained by contrast enhanced computed tomography (CT) or magnetic resonance (MR) imaging. Specific clinical issues include: a) differentiating between tumor recurrence and tissue necrosis, b) identifying the boundaries of low grade brain tumors with a """"""""normal"""""""" blood- brain barrier (BBB), c) localizing the infiltrating margin of a high grade tumor that does not contrast enhance on CT or MR, d) providing a better noninvasive estimate of tumor malignancy, and e) providing a better noninvasive estimate of treatment response. The advantages of ACPC and AIB for brain tumor imaging are based on: a) a low and more uniform uptake in normal brain compared to FDG; b) a greater tumor-to-normal brain uptake ratio(contrast) than either FDG or methionine; and c) a greater specificity in identifying viable tumor tissue than contrast enhanced CT or MR imaging. Two different experimental brain tumors will be studied that reflect a range of biological differences observed in patients with brain tumors: 1) W256a tumors have a """"""""low"""""""" rate of cell proliferation, grow """"""""slowly"""""""" and have """"""""low"""""""" vascular permeability; 2) W256b tumors have a """"""""high"""""""" rate of cell proliferation, grow """"""""rapidly"""""""" and have """"""""high"""""""" vascular permeability. The animal studies are designed to"""""""" a) define an appropriate kinetic model of ACPC and AIB uptake in tumor and brain that is based on the tissue and blood time-activity profiles of these amino acids (aim 1); b) define the quantitative and spatial relationships between ACPC, AIB, FDG and gallium- DTPA uptake within i.c. tumors and adjacent brain using triple-label quantitative autoradiographic techniques, and to assess the effect of local vascular permeability, cell proliferation (labeling index), and tissue morphology (e.g.,necrosis) on tumor imaaging (aim2); c) assess the effects of radiotherapy and chemotherapy on the quantitative and spatial relationships between ACPC, AIB, FDG and gallium-DTPA uptake within i.c. tumors and adjacent brain using triple-label quantitative autoradiography, and correlate these results with local measurements of vascular permeability, tumor cell proliferation and tissue morphology (aim 3). The results from this proposal will provide a basis for deciding whether to initiate similar studies in patients with brain tumors using [11C]-ACPC or [11C]-AIB and PET, and these results will provide data for establishing appropriate protocols for patient studies.
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