Convenient solid-phase synthesis of diethylenetriaminepenta-acetic acid (DTPA)- conjugated cyclic RGD peptide analogues.

Solid-phase synthesis of radiometal chelator-conjugated peptides can facilitate the creation of radioactive peptide libraries to be utilized in high throughput in vivo screening of targeted nuclear-imaging agents. In this study, a new diethylenetriaminepentaacetic acid (DTPA) derivative, 1-(p-succinamidobenzyl)- DTPA penta-t-butyl ester [DTPA(But)(5)-Bz-NH-SA], and its precursor molecule, 1-(p-aminobenzyl)- DTPA penta-t-butyl ester (DTPA(But)(5)-Bz-NH(2)), were applied to the solid-phase synthesis of DTPA-conjugated cyclic peptides containing the Arg-Gly-Asp (RGD) motif with high efficiency. The resulting conjugates, DTPA-Bz-NH-SA-c(Lys-Arg-Gly-Asp-phe) [DTPA-Bz-NH-SA-c(KRGDf)] and DTPA-Bz-NHc( Glu-Arg-Gly-Asp-phe) [DTPA-Bz-NH-c(KRGDf)], demonstrated similar in vitro biologic activities as their corresponding parent peptides. (111)In-labeled, DTPA-conjugated RGD peptides showed selective binding to integrin alphavbeta3 in human melanoma M21 tumors grown in nude mice. Furthermore, (111)In-DTPABz- NH-c(ERGDf) showed lower retention in the liver and the kidney than (111)In-DTPA-Bz-NH-SAc( KRGDf) did, which contributed to higher target to nontarget ratio for (111)In-DTPA-Bz-NH-c(ERGDf). The method reported here can be extended to the construction of peptide libraries containing DTPA for high throughput in vitro and in vivo screening of molecularly targeted imaging agents.