Département de chimie moléculaire

Introduction: The $\alpha$V$\beta$3 integrin is a well-known transmembrane receptor involved in tumor invasion, angiogenesis and metastasis. Our aim was to evaluate a novel positron emission tomog. (PET) probe, 64Cu-cyclam-RAFT-c(-RGDfK-)4, for noninvasive visualization and quantification of $\alpha$V$\beta$3 integrin expression. Methods: RAFT-c(-RGDfK-)4, a tetrameric cyclic Arg-Gly-Asp (RGD)-based peptide, was conjugated with a bifunctional chelator, 1,4,8,11-tetraazacyclotetradecane (cyclam), radiolabeled with the positron emitter 64Cu and evaluated in vitro by cell binding and competitive inhibition assays and in vivo by biodistribution and receptor blocking studies, and PET imaging. The following cell lines, human embryonic kidney HEK293($\beta$1) [$\alpha$V$\beta$3-neg.] and HEK293($\beta$3) [$\alpha$V$\beta$3-overexpressing] and human glioblastoma U87MG [naturally expressing $\alpha$V$\beta$3], together with their s.c. xenografts in athymic nude mice, were used for the present study. The expression levels of $\alpha$V$\beta$3 on these cell lines and tumor xenografts were analyzed by flow cytometry and sodium dodecyl sulfate-polyacrylamide gel electrophoresis/autoradiog., resp. Results: 64Cu-cyclam-RAFT-c(-RGDfK-)4 demonstrated the in vitro and in vivo specificity for the $\alpha$V$\beta$3 integrin and displayed rapid blood clearance, predominantly renal excretion and low uptake in nontumor tissues. Tumor uptake of 64Cu-cyclam-RAFT-c(-RGDfK-)4 (3 h postinjection) in HEK293($\beta$3) (high levels of $\alpha$V$\beta$3), U87MG (moderate levels of $\alpha$V$\beta$3) and HEK293($\beta$1) (undetectable levels of $\alpha$V$\beta$3) tumors was 9.35{%}±1.19{%}, 3.46{%}±0.45{%} and 1.18{%}±0.30{%} injected dose per g, resp., with a strong and pos. correlation with the tumor $\alpha$V$\beta$3 expression levels (correlation coeff.=0.967; P{\textless}.0001). Positron emission tomog. images showed that $\alpha$V$\beta$3-pos. tumors were clearly visualized with high tumor-to-background contrast, and agreed well with the biodistribution results. Conclusion: 64Cu-cyclam-RAFT-c(-RGDfK-)4 exhibits potential for noninvasively quantifying $\alpha$V$\beta$3 expression. [on SciFinder(R)]