Stabilization Strategies for Linear Minigastrin Analogues: Further Improvements via the Inclusion of Proline into the Peptide Sequence
In: Journal of Medicinal Chemistry, Jg. 63 (2020-11-01), Heft 23, S. 14668-14679
Online
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Zugriff:
Minigastrin (MG) analogues, known for their high potential to target cholecystokinin-2 receptor (CCK2R) expressing tumors, have limited clinical applicability due to low enzymatic stability. By introducing site-specific substitutions within the C-terminal receptor-binding sequence, reduced metabolization and improved tumor targeting can be achieved. In this work, the influence of additional modification within the N-terminal sequence has been explored. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CCK2R ligands with proline substitution at different positions were synthesized. Substitution did not affect CCK2R affinity, and the conjugates labeled with indium-111 and lutetium-177 showed a high enzymatic stability in different incubation media as well as in vivo (57-79% intact radiopeptide in blood of BALB/c mice at 1 h p.i.) combined with enhanced tumor uptake (29-46% IA/g at 4 h in xenografted BALB/c nude mice). The inclusion of Pro contributes significantly to the development of CCK2R ligands with optimal targeting properties for application in targeted radiotherapy.
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Stabilization Strategies for Linear Minigastrin Analogues: Further Improvements via the Inclusion of Proline into the Peptide Sequence
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Autor/in / Beteiligte Person: | Klingler, Maximilian ; Castel, Hélène ; Elisabeth von Guggenberg ; Desrues, Laurence ; Gandolfo, Pierrick ; Rangger, Christine ; Anton Amadeus Hörmann |
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Zeitschrift: | Journal of Medicinal Chemistry, Jg. 63 (2020-11-01), Heft 23, S. 14668-14679 |
Veröffentlichung: | American Chemical Society, 2020 |
Medientyp: | unknown |
ISSN: | 1520-4804 (print) ; 0022-2623 (print) |
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