18F-Labeled Galacto and PEGylated RGD Dimers for PET Imaging of αvβ3 Integrin Expression

In vivo imaging of alpha(v)beta(3) has important diagnostic and therapeutic applications. F-18-Galacto-arginine-glycine-aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin alpha(v)beta(3) expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin alpha(v)beta(3)-binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used F-18-galacto-RGD. RGD monomers and dimers were coupled with galacto or PEG(3) linkers, and labeled with F-18 using 4-nitrophenyl 2-F-18-fluoropropionate (F-18-NFP) or N-succinimidyl 4-F-18-fluorobenzoate as a prosthetic group. The newly developed tracers were evaluated by cell-based receptor-binding assay, biodistribution, and small-animal PET studies in a subcutaneous U87MG glioblastoma xenograft model. Starting with F-18-F-, the total reaction time for F-18-FP-SRGD2 and F-18-FP-PRGD2 is about 120 min. The decay-corrected radiochemical yields for F-18-FP-SRGD2 and F-18-FP-PRGD2 are 52 +/- 9% and 80 +/- 7% calculated from F-18-NFP. Noninvasive small-animal PET and direct tissue sampling experiments demonstrated that the dimeric RGD peptides had significantly higher tumor uptake as compared to F-18-galacto-RGD. Dimeric RGD peptide tracers with relatively high tumor integrin-specific accumulation and favorable in vivo kinetics may have the potential to be translated into clinic for integrin alpha(v)beta(3) imaging.