Rapid and high-yield solution-phase synthesis of DOTA-Tyr3-octreotide and DOTA-Tyr3-octreotate using unprotected DOTA

An improved method for the solution-phase derivatization of Tyr3-Lys5(Dde)-octreotide (TOC(Dde)) and Tyr3-Lys5(Dde)-octreotate (TATE(Dde)) with the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-N′,N″,N‴,N⁗-tetraacetic acid) has been developed. The fully protected parent peptides were assembled via solid-phase peptide synthesis (SPPS) using Fmoc-strategy. After cleavage from the solid support, disulfide bond formation was carried out using H2O2. Both TOC(Dde) and TATE(Dde) were successfully coupled with DOTA in the presence of NHS, EDCI and DIPEA in a water/DMF solvent system. Yields of the coupling reaction were >98% within only 2 h with no detectable formation of sideproducts. This method for the preparation of DOTATOC, DOTATATE and other DOTA-peptide conjugates is therefore a rapid and economic alternative to the currently used methods.