Radiolabeled Cyclic RGD Peptides as Integrin αvβ3-Targeted Radiotracers: Maximizing Binding Affinity via Bivalency

Integrin αvβ3 plays a significant role in tumor angiogenesis and is a receptor for the extracellular matrix proteins with the exposed arginine-glycine-aspartic (RGD) tripeptide sequence. These include vitronectin, fibronectin, fibrinogen, lamin, collagen, Von Willibrand's factor, osteoponin, and adenovirus particles. Integrin αvβ3 is expressed at low levels on epithelial cells and mature endothelial cells, but it is overexpressed on the activated endothelial cells of tumor neovasculature and some tumor cells. The restricted expression of integrin αvβ3 during tumor growth, invasion, and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. Over the past decade, many radiolabeled linear and cyclic RGD peptide antagonists have been evaluated as integrin αvβ3-targeted radiotracers. Significant progress has been made on their use for imaging integrin αvβ3-positive tumors by SPECT or PET. Among the radiotracers evaluated in preclinical tumor-bearing models, [18F]Galacto-RGD (2-[18F]fluoropropanamide c(RGDfK(SAA); SAA = 7-amino-l-glyero-l-galacto-2,6-anhydro-7-deoxyheptanamide) and [18F]-AH111585 are currently under clinical investigation for visualization of integrin αvβ3 expression in cancer patients. However, their low tumor uptake, high cost, and lack of preparative modules for routine radiosynthesis will limit their continued clinical application. Thus, there is a continuing need for more efficient integrin αvβ3-targeted radiotracers that are readily prepared from a kit formulation without further postlabeling purification. This article will focus on different approaches to maximize the targeting capability of cyclic RGD peptides and to improve the radiotracer excretion kinetics from noncancerous organs. Improvement of tumor uptake and tumor-to-background ratios is important for early detection of integrin αvβ3-positive tumors and/or noninvasive monitoring of therapeutic efficacy of antiangiogenic therapy.