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The overexpression of one or more somatostatin receptors (SST_1–5R) in human tumors has provided an opportunity for diagnosis and therapy with somatostatin-like radionuclide carriers. The application of “pansomatostatin” analogs is expected to broaden the clinical indications and upgrade the diagnostic/therapeutic efficacy of currently applied SST₂R-prefering radioligands. In pursuit of this goal, we now introduce two bicyclic somatostatin-14 (SS14) analogs, AT5S (DOTA-Ala¹-Gly²-c[Cys³-Lys⁴-Asn⁵-c[Cys⁶-Phe⁷-DTrp⁸-Lys⁹-Thr¹⁰-Cys¹¹]-Thr¹²-Ser¹³-Cys¹⁴]) and AT6S (DOTA-Ala¹-Gly²-c[Cys³-Lys⁴-c[Cys⁵-Phe⁶-Phe⁷-DTrp⁸-Lys⁹-Thr¹⁰-Phe¹¹-Cys¹²]-Ser¹³-Cys¹⁴]), suitable for labeling with trivalent radiometals and designed to sustain in vivo degradation. Both AT5S and AT6S and the respective [¹¹¹In]In-AT5S and [¹¹¹In]In-AT6S were evaluated in a series of in vitro assays, while radioligand stability and biodistribution were studied in mice. The 8/12-mer bicyclic AT6S showed expanded affinity for all SST_1–5R and agonistic properties at the SST₂R, whereas AT5S lost all affinity to SST_1–5R. Both [¹¹¹In]In-AT5S and [¹¹¹In]In-AT6S remained stable in the peripheral blood of mice, while [¹¹¹In]In-AT6S displayed low, but specific uptake in AR4-2J tumors and higher uptake in HEK293-SST₃R tumors in mice. In summary, high radioligand stability was acquired by the two disulfide bridges introduced into the SS14 motif, but only the 8/12-mer ring AT6S retained a pansomatostatin profile. In consequence, [¹¹¹In]In-AT6S targeted SST₂R-/SST₃R-positive xenografts in mice. These results call for further research on pansomatostatin-like radioligands for cancer theranostics. Full article

Somatostatin analogues are useful pharmaceuticals in peptide receptor radionuclide therapy. In previous studies, we analyzed a new bicyclic somatostatin analogue (BCS) in connection with Cu(II) ions. Two characteristic sites were present in the peptide chain: the receptor- and the metal-binding site. We have already shown that this ligand can form very stable imidazole complexes with the metal ion. In this work, our aim was to characterize the intramolecular interaction that occurs in the peptide molecule. Therefore, we analyzed the coordination abilities of two cyclic ligands, i.e., P1 only with the metal binding site and P2 with both sites, but without the disulfide bond. Furthermore, we used magnetic circular dichroism (MCD) spectroscopy to better understand the coordination process. We applied this method to analyze spectra of P1, P2, and BCS, which we have described previously. Additionally, we analyzed the MCD spectra of P3 ligand, which has only the receptor binding site in its structure. We have unequivocally shown that the presence of the Phe-Trp-Lys-Thr motif and the disulfide bond significantly increases the metal binding efficiency. Full article