Amide-to-Triazole Switch in Somatostatin-14-Based Radioligands: Impact on Receptor Affinity and In Vivo Stability

Xabier Guarrochena; Panagiotis Kanellopoulos; Anna Stingeder; Lisa-Maria Rečnik; Irene V J Feiner; Marie Brandt; Wolfgang Kandioller; Theodosia Maina; Berthold A Nock; Thomas L Mindt

doi:10.3390/pharmaceutics16030392

Amide-to-Triazole Switch in Somatostatin-14-Based Radioligands: Impact on Receptor Affinity and In Vivo Stability

Pharmaceutics. 2024 Mar 13;16(3):392. doi: 10.3390/pharmaceutics16030392.

Authors

Xabier Guarrochena^{1

2

3

4}, Panagiotis Kanellopoulos⁵, Anna Stingeder^{3

4}, Lisa-Maria Rečnik^{1

3

4}, Irene V J Feiner^{1

3

4}, Marie Brandt^{1

3

4}, Wolfgang Kandioller⁶, Theodosia Maina⁵, Berthold A Nock⁵, Thomas L Mindt^{1

3

4

6

7}

Affiliations

¹ Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
² Vienna Doctoral School in Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria.
³ Ludwig Boltzmann Institute Applied Diagnostics, AKH Wien c/o Sekretariat Nuklearmedizin, Währinger Gürtel 18-20, 1090 Vienna, Austria.
⁴ Department of Biomedical Imaging and Image Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
⁵ Molecular Radiopharmacy, INRaSTES, NCSR "Demokritos", 15341 Athens, Greece.
⁶ Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Str. 42, 1090 Vienna, Austria.
⁷ Joint Applied Medicinal Radiochemistry Facility, University of Vienna and Medical University of Vienna, 1090 Vienna, Austria.

Abstract

The use of metabolically stabilized, radiolabeled somatostatin (SST) analogs ([⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-TATE/TOC/NOC) is well established in nuclear medicine. Despite the pivotal role of these radioligands in the diagnosis and therapy of neuroendocrine tumors (NETs), their inability to interact with all five somatostatin receptors (SST_1-5R) limits their clinical potential. [¹¹¹In]In-AT2S is a radiolabeled DOTA-conjugate derived from the parent peptide SST-14 that exhibits high binding affinity to all SSTR subtypes, but its poor metabolic stability represents a serious disadvantage for clinical use. In order to address this issue, we have replaced strategic trans-amide bonds of [¹¹¹In]In-AT2S with metabolically stable 1,4-disubstituted 1,2,3-triazole bioisosteres. From the five cyclic triazolo-peptidomimetics investigated, only [¹¹¹In]In-XG1 combined a preserved nanomolar affinity for the SST_1,2,3,5R subtypes in vitro and an improved stability in vivo (up to 17% of intact peptide 5 min postinjection (pi) versus 6% for [¹¹¹In]In-AT2S). The involvement of neprilysin (NEP) in the metabolism of [¹¹¹In]In-XG1 was confirmed by coadministration of Entresto^®, a registered antihypertensive drug, in vivo releasing the selective and potent NEP-inhibitor sacubitrilat. A pilot SPECT/CT imaging study conducted in mice bearing hSST₂R-positive xenografts failed to visualize the xenografts due to the pronounced kidney uptake (>200% injected activity (IA)/g at 4 h pi), likely the result of the formation of cationic metabolites. To corroborate the imaging data, the tumors and the kidneys were excised and analyzed with a γ-counter. Even if receptor-specific tumor uptake for [¹¹¹In]In-XG1 could be confirmed (1.61% IA/g), further optimization is required to improve its pharmacokinetic properties for radiotracer development.

Keywords: 1,4-disubstituted 1,2,3-triazole; Entresto®; amide-to-triazole substitution; bioisosteres; metabolic stability; neprilysin; pansomatostatin; peptide-based radiotracer; somatostatin; triazolo-peptidomimetic.

Abstract

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