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Article

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

by
Aikaterini Tatsi
1,2,
Theodosia Maina
1,*,
Beatrice Waser
3,
Eric P. Krenning
4,
Marion de Jong
5,†,
Jean Claude Reubi
3,
Paul Cordopatis
2,† and
Berthold A. Nock
1
1
Molecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, GR-15341 Athens, Greece
2
Department of Pharmacy, University of Patras, GR-26500 Patras, Greece
3
Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland
4
Cyclotron Rotterdam BV, Erasmus MC, 3015 Rotterdam, The Netherlands
5
Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
†
These authors are deceased.
Int. J. Mol. Sci. 2024, 25(3), 1921; https://doi.org/10.3390/ijms25031921
Submission received: 28 December 2023 / Revised: 25 January 2024 / Accepted: 27 January 2024 / Published: 5 February 2024
(This article belongs to the Special Issue Bioactive Peptides in Human Health and Disease 2.0)
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Abstract

The overexpression of one or more somatostatin receptors (SST1–5R) 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 SST1–5R and agonistic properties at the SST2R, whereas AT5S lost all affinity to SST1–5R. 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.
Keywords: DOTA-conjugated somatostatin; [111In]In-radioligand; bicyclic somatostatin; metabolic stability; tumor targeting; theranostics DOTA-conjugated somatostatin; [111In]In-radioligand; bicyclic somatostatin; metabolic stability; tumor targeting; theranostics

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MDPI and ACS Style

Tatsi, A.; Maina, T.; Waser, B.; Krenning, E.P.; de Jong, M.; Reubi, J.C.; Cordopatis, P.; Nock, B.A. Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [111In]In-Radioligands: Synthesis and Preclinical Profile. Int. J. Mol. Sci. 2024, 25, 1921. https://doi.org/10.3390/ijms25031921

AMA Style

Tatsi A, Maina T, Waser B, Krenning EP, de Jong M, Reubi JC, Cordopatis P, Nock BA. Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [111In]In-Radioligands: Synthesis and Preclinical Profile. International Journal of Molecular Sciences. 2024; 25(3):1921. https://doi.org/10.3390/ijms25031921

Chicago/Turabian Style

Tatsi, Aikaterini, Theodosia Maina, Beatrice Waser, Eric P. Krenning, Marion de Jong, Jean Claude Reubi, Paul Cordopatis, and Berthold A. Nock. 2024. "Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [111In]In-Radioligands: Synthesis and Preclinical Profile" International Journal of Molecular Sciences 25, no. 3: 1921. https://doi.org/10.3390/ijms25031921

APA Style

Tatsi, A., Maina, T., Waser, B., Krenning, E. P., de Jong, M., Reubi, J. C., Cordopatis, P., & Nock, B. A. (2024). Bis(Disulfide)-Bridged Somatostatin-14 Analogs and Their [111In]In-Radioligands: Synthesis and Preclinical Profile. International Journal of Molecular Sciences, 25(3), 1921. https://doi.org/10.3390/ijms25031921

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