Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [¹¹¹In]In-Radioligands: Synthesis and Preclinical Profile

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.