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 [¹²⁵I-c(RGDyK), ⁷⁷Br-c(RGDyK), [¹²⁵I]SIB-c(RGDfK), [⁷⁷Br]SBrB-c(RGDfK), [¹²⁵I]SIB-EG₂-c(RGDfK), and [⁷⁷Br]SBrB-EG₂-c(RGDfK)] were designed, prepared, and evaluated. In these initial studies, ⁷⁷Br (t_1/2=57.0 h) and ¹²⁵I (t_1/2=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 [¹²⁵I]N-succinimidyl 3-iodobenzoate ([¹²⁵I]SIB) or [⁷⁷Br]N-succinimidyl 3-bromobenzoate ([⁷⁷Br]SBrB). Measurement of the partition coefficients, integrin binding assay, and biodistribution experiments in tumor-bearing mice were performed. ¹²⁵I and ⁷⁷Br labeling were successfully performed using similar methods, and in vitro characteristics and biodistributions were similar between the ¹²⁵I-labeled and corresponding ⁷⁷Br-labeled peptides. [¹²⁵I]SIB- and [⁷⁷Br]SBrB-conjugated RGD peptides showed higher partition coefficients, lower tumor uptakes, and higher intestinal uptake than ¹²⁵I-c(RGDyK) and ⁷⁷Br-c(RGDyK). [¹²⁵I]SIB-EG₂-c(RGDfK) and [⁷⁷Br]SBrB-EG₂-c(RGDfK), which possess an ethylene glycol linker, decreased lipophilicity and uptake in intestine compared with [¹²⁵I]SIB-c(RGDfK) and [⁷⁷Br]SBrB-c(RGDfK), which possess no linker. However, the improvement in biodistribution of [¹²⁵I]SIB-EG₂-c(RGDfK) and [⁷⁷Br]SBrB-EG₂-c(RGDfK)] was insufficient. In conclusion, directly radiohalogenated c(RGDyK) peptides are potentially more useful for tumor imaging and therapy than indirectly radiohalogenated ones.

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