PET Reagents for Normal and Tumor Tissue Hypoxia

DESCRIPTION (provided by applicant): Disruption of O2 gradients in normal tissues creates major medical problems including cardiovascular disease, stroke, diabetes, liver and kidney damage and organ transplant failure. Steep O2 gradients in tumors protect tumor cells from cytotoxic therapies and create more aggressive tumors. Measurements of O2 gradients are clearly needed. This study proposes F-18 positron emission tomography (PET) reagents based on Hypoxyprobe(TM) markers for non-invasive assays of normal and malignant tissue hypoxia. Hypoxyprobe(TM) PET markers will have: high water solubility; chemical stability; universal tissue distribution; short plasma half-life; low toxicity; and, high tissue adduct stability. Hypoxyprobe(TM) kits are already marketed for studies of tissue hypoxia by flow cytometry, ELISA and immunohistology. PET reagents would be an exciting addition. The synthesis of fluorinated Hypoxyprobe(TM) analogues will be optimized and promising analogues tested in single cell suspensions and in multicellular spheroid systems for their ability to discriminate cells at different levels of hypoxia. Binding of the fluorinated analogues will be quantitated immunochemically by means of monoclonal antibodies raised against the Hypoxyprobe(TM) analogues. Analogues whose synthesis is rapid and clean with respect to fluoride incorporation and whose ability to discriminate hypoxic cells is optimal will be tested in animal PET facilities in Phase II STTR studies. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE