18F-labeled galacto and PEGylated RGD dimers for PET imaging of αvβ3 integrin expression

Purpose—In vivo imaging of αvβ3 has important diagnostic and therapeutic applications. 18F-Galacto-arginine–glycine–aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin αvβ3 expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin αvβ3-binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used 18F-galacto-RGD. Procedures—RGD monomers and dimers were coupled with galacto or PEG3 linkers, and labeled with 18F using 4-nitrophenyl 2-18F-fluoropropionate (18F-NFP) or N-succinimidyl 4-18F-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. Results—Starting with 18F-F−, the total reaction time for 18F-FP-SRGD2 and 18F-FP-PRGD2 is about 120 min. The decay-corrected radiochemical yields for 18F-FP-SRGD2 and 18F-FP-PRGD2 are 52±9 % and 80±7 % calculated from 18F-NFP. Noninvasive small-animal PET and direct tissue sampling experiments demonstrated that the dimeric RGD peptides had significantly higher tumor uptake as compared to 18F-galacto-RGD. Conclusion—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 αvβ3 imaging