Overexpression of alpha(v)beta(3) integrin on the surfaces of tumor cells and activated endothelial cells as compared to normal cells and rest endothelial cells implicates the application of radiolabeled alpha(v)beta(3) integrin antagonist for imaging of alpha(v)beta(3) expression levels in alpha(v)beta(3) positive tumors. The goal of this proposal is to develop copper-64 (t1/2 = 12.7 h) labeled RGD peptide antagonists of alpha(v)beta(3) integrin for breast cancer targeting by means of positron emission tomography (PET). We hypothesize that conjugation and radiolabeling of RGD peptides will have significant effect on the receptor binding affinity and specificity, as well as the in vivo pharmacokinetics of these radiotracers. To make the tracers clinically applicable for patient segmentation based upon alpha(v)beta(3) integrin expression levels, systematic studies have to be performed to optimize the tracer in such a way that the tracer will have fast and high yield radiolabeling, in vivo stability against transchelation, and high receptor binding affinity and specificity. The radiotracer should also be designed to have satisfactory in vivo pharmacokinetics for high quality imaging: high tumor-to-normal tissue ratio, fast circulation clearance, low kidney uptake and fast renal clearance, as well as avoiding hepatobiliary excretion. The research proposed here is to: 1) develop and optimize copper-64 labeled RGD peptides for breast cancer tumor targeting; and 2) correlate the magnitude of tumor uptake with tumor integrin density levels in preclinical animal models. The success of this research will facilitate the rapid translation of this laboratory work into clinical applications, since the features of small animal PET imaging studies closely reflect the settings of a clinical PET study for human beings. We anticipate that noninvasive serial studies of alpha(v)beta(3) expression and functional activity using PET will become an important tool to evaluate the role of alpha(v)beta(3) integrin during tumor progression and metastasis.
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