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This work is devoted to the large-scale solid-phase synthesis (SPS) of Atosiban, Mpa1-D-Tyr(OEt)-Ile-Thr-Asn-Cys6-Pro-Orn-Gly-NH2 cyclic 1,6 disulfide, the only clinically used oxytocin receptor antagonist. The conditions have been selected for the closure of the disulfide bond (S–S) in the Atosiban molecule both in the solution and solid phase with the minimal formation of by-products. A comparative assessment of the formation of the S–S bond was carried out under various conditions. The formation of by-products during the closure of the disulfide bond has been studied both in solution and on the polymer support. The developed technique allows for the synthesis of Atosiban on an enlarged scale (10–20 mmol) involving the cyclization of a protected intermediate with the formation of the S–S bond during solid-phase synthesis with the minimal formation of by-products.

This study aims at analyzing complexation properties of two new short somatostatin analogues, their synthesis, radiolabeling with 44Sc, 207Bi, and 152Eu and stability in vitro. Short tetrapeptide Phe‐d‐Trp‐Lys‐Thr and pentapeptide Thz‐Phe‐d‐Trp‐Lys‐Thr were first conjugated with the DOTA macrocyclic chelator. These conjugates were radiolabeled with 44Sc, 207Bi, and 152Eu and characterized by thin‐layer chromatography (TLC) and HPLC. The radiochemical purity was measured using digital autoradiography and gamma spectrometry. Optimum conditions of DOTA‐conjugate labeling were found: 0.1mM, pH 8.0 to 8.4 at 90°C for DOTA‐tetrapeptide complexes with 207Bi and 152Eu; 0.05mM, pH 4.0 to 5.0 at 90°C for 44Sc‐DOTA‐tetrapeptide; 0.2mM, pH 4.0 to 5.0 at 90°C for 44Sc‐DOTA‐pentapeptide. Complexes of DOTA‐pentapeptide with 207Bi and 152Eu of radiochemical purity more than 95% were probably unstable at temperature higher than 37°C and were obtained at 37°C, pH 8.0 to 8.4 within 4 days. Mass spectra of the Eu‐DOTA‐pentapeptide revealed the presence of small fragments of the pentapeptide conjugate in the complex solution. in vitro stability studies were performed in saline in the presence of serum proteins and biologically relevant metal cations. All complexes demonstrated no cation release in vitro within 1 to 4 hours.

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