Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [In]In-Radioligands: Synthesis and Preclinical Profile.

The overexpression of one or more somatostatin receptors (SSTR) 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 SSTR-prefering radioligands. In pursuit of this goal, we now introduce two bicyclic somatostatin-14 (SS14) analogs, AT5S (DOTA-Ala-Gly-c[Cys-Lys-Asn-c[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-Ser-Cys]) and AT6S (DOTA-Ala-Gly-c[Cys-Lys-c[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-Ser-Cys]), suitable for labeling with trivalent radiometals and designed to sustain in vivo degradation. Both AT5S and AT6S and the respective [In]In-AT5S and [In]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 SSTR and agonistic properties at the SSTR, whereas AT5S lost all affinity to SSTR. Both [In]In-AT5S and [In]In-AT6S remained stable in the peripheral blood of mice, while [In]In-AT6S displayed low, but specific uptake in AR4-2J tumors and higher uptake in HEK293-SSTR 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, [In]In-AT6S targeted SSTR-/SSTR-positive xenografts in mice. These results call for further research on pansomatostatin-like radioligands for cancer theranostics.