Radiolabeled Cyclic RGD Peptide Bioconjugates as Radiotracers Targeting Multiple Integrins

Angiogenesis is a requirement for tumor growth and metastasis. The angiogenic process depends on vascular endothelial cell migration and invasion, and is regulated by various cell adhesion receptors. Integrins are such a family of receptors that facilitate the cellular adhesion to and migration on extracellular matrix proteins in the intercellular spaces and basement membranes. Among 24 members of the integrin family, αvβ3 is studied most extensively for its role in tumor angiogenesis and metastasis. The αvβ3 is expressed at relatively low levels on epithelial cells and mature endothelial cells, but it is highly expressed on the activated endothelial cells of tumor neovasculature and some tumor cells. This restricted expression makes αvβ3 an excellent target to develop antiangiogenic drugs and diagnostic molecular imaging probes. Since αvβ3 is a receptor for extracellular matrix proteins with one or more RGD tripeptide sequence, many radiolabeled cyclic RGD peptides have been evaluated as "αvβ3-targeted" radiotracers for tumor imaging over the past decade. This article will use the dimeric and tetrameric cyclic RGD peptides developed in our laboratories as examples to illustrate basic principles for development of αvβ3-targeted radiotracers. It will focus on different approaches to maximize the radiotracer tumor uptake and tumor/background ratios. This article will also discuss some important assays for preclinical evaluations of integrin-targeted radiotracers. In general, multimerization of cyclic RGD peptides increases their integrin binding affinity and the tumor uptake and retention times of their radiotracers. Regardless of their multiplicity, the capability of cyclic RGD peptides to bind other integrins (namely, αvβ5, α5β1, α6β4, α4β1, and αvβ6) is expected to enhance the radiotracer tumor uptake due to the increased integrin population. The results from preclinical and clinical studies clearly show that radiolabeled cyclic RGD peptides (such as (99m)Tc-3P-RGD2, (18)F-Alfatide-I, and (18)F-Alfatide-II) are useful as the molecular imaging probes for early cancer detection and noninvasive monitoring of the tumor response to antiangiogenic therapy.