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