Comparison of Radioiodine- or Radiobromine-Labeled RGD Peptides between Direct and Indirect Labeling Methods.

Radiolabeled cyclic peptides containing the (Arg-Gly-Asp) RGD sequence for use in positron emission tomography (PET) imaging, single-photon emission computed tomography (SPECT) imaging, and targeted radionuclide therapy of cancer have been reported. In this study, RGD was used as a model carrier peptide for diagnosis and therapy of cancer. To evaluate the characteristics of radiohalogen-labeled peptides, several kinds of labeled RGD peptides [I-c(RGDyK), Br-c(RGDyK), [I]SIB-c(RGDfK), [Br]SBrB-c(RGDfK), [I]SIB-EG-c(RGDfK), and [Br]SBrB-EG-c(RGDfK)] were designed, prepared, and evaluated. In these initial studies, Br (t=57.0 h) and I (t=59.4 d) were used because of their longer half-lives. Precursor peptides were synthesized using a standard 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase methodology. Radiolabeled peptides were prepared by chloramine-T method or conjugation of RGD peptides with [I]N-succinimidyl 3-iodobenzoate ([I]SIB) or [Br]N-succinimidyl 3-bromobenzoate ([Br]SBrB). Measurement of the partition coefficients, integrin binding assay, and biodistribution experiments in tumor-bearing mice were performed. I and Br labeling were successfully performed using similar methods, and in vitro characteristics and biodistributions were similar between the I-labeled and corresponding Br-labeled peptides. [I]SIB- and [Br]SBrB-conjugated RGD peptides showed higher partition coefficients, lower tumor uptakes, and higher intestinal uptake than I-c(RGDyK) and Br-c(RGDyK). [I]SIB-EG-c(RGDfK) and [Br]SBrB-EG-c(RGDfK), which possess an ethylene glycol linker, decreased lipophilicity and uptake in intestine compared with [I]SIB-c(RGDfK) and [Br]SBrB-c(RGDfK), which possess no linker. However, the improvement in biodistribution of [I]SIB-EG-c(RGDfK) and [Br]SBrB-EG-c(RGDfK)] was insufficient. In conclusion, directly radiohalogenated c(RGDyK) peptides are potentially more useful for tumor imaging and therapy than indirectly radiohalogenated ones.