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

The overexpression of one or more somatostatin receptors (SST 1-5 R) 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 SST 2 R-prefering radioligands. In pursuit of this goal, we now introduce two bicyclic somatostatin-14 (SS14) analogs, AT5S (DOTA-Ala 1 -Gly 2 -c[Cys 3 -Lys 4 -Asn 5 -c[Cys 6 -Phe 7 -DTrp 8 -Lys 9 -Thr 10 -Cys 11 ]-Thr 12 -Ser 13 -Cys 14 ]) and AT6S (DOTA-Ala 1 -Gly 2 -c[Cys 3 -Lys 4 -c[Cys 5 -Phe 6 -Phe 7 -DTrp 8 -Lys 9 -Thr 10 -Phe 11 -Cys 12 ]-Ser 13 -Cys 14 ]), suitable for labeling with trivalent radiometals and designed to sustain in vivo degradation. Both AT5S and AT6S and the respective [ 111 In]In-AT5S and [ 111 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 SST 1-5 R and agonistic properties at the SST 2 R, whereas AT5S lost all affinity to SST 1-5 R. Both [ 111 In]In-AT5S and [ 111 In]In-AT6S remained stable in the peripheral blood of mice, while [ 111 In]In-AT6S displayed low, but specific uptake in AR4-2J tumors and higher uptake in HEK293-SST 3 R 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, [ 111 In]In-AT6S targeted SST 2 R-/SST 3 R-positive xenografts in mice. These results call for further research on pansomatostatin-like radioligands for cancer theranostics.