Truncated NPY-based NPY(Y1)R-specific radiopeptides: Improved in vivo PET tumor imaging by application of peptidase inhibitors
Notice bibliographique
Résumé
The neuropeptide Y receptor subtype 1 (NPY(Y 1 )R) exhibits high expression rates on human breast cancer and is therefore an important target structure for the sensitive and specific visualization and characterization of the disease by Positron Emission Tomography (PET). However, imaging of this receptor type has been of limited success so far due to the low stability of peptide-based NPY-derived NPY(Y 1 )R-specific radiotracer candidates due to in vivo degradation. Given the challenges in stabilizing these agents, our study sought to explore whether the stability of NPY(Y 1 )R-specific radiopeptides could be enhanced. We aimed to achieve this by either modifying the peptide structure with various molecular scaffolds or by applying peptidase inhibitors. This evaluation aimed to identify the optimal approach for achieving effective NPY(Y 1 )R-specific imaging in the following. To validate our approach, we systematically investigated four new truncated 68 Ga-labeled analogs of NPY and the reference compound [ 68 Ga]Ga-[Lys 4 (N ε -DOTA)]BVD15, bearing different molecular scaffolds such as a DOTA or NODA-GA chelator, a 4-APipAc linker, a Bip unit, and an N -terminal Lys(lauryl) group. The four new radiotracers as well as the reference compound were obtained in high chemical and radiochemical yields with molar activities of 33–39 GBq/μmol. The radiopeptides exhibited varying log D 7.4 values, ranging from −3.37 ± 0.09 to +0.35 ± 0.11, and showed different levels of stability in human serum and liver microsomes, depending on their molecular structure. Subsequently, the influence of the peptidase inhibitors actinonin, phosphoramidon, captopril and E−64 on the in vitro stability of the radiotracers was investigated. In these studies, only actinonin demonstrated a positive effect on the stability of all radiopeptides. In contrast, phosphoramidon yielded variable results, and neither captopril nor E−64 showed a significant stabilizing effect. Consequently, the effect of actinonin administration on the in vivo PET/CT imaging results of the most promising ligand [ 68 Ga]Ga-[Lys 4 (N ε -NODA-GA)]BVD15 ([ 68 Ga]Ga- 2 ) was investigated in a T47D tumor-bearing xenograft mouse model, followed by ex vivo biodistribution studies. In these experiments, the administration of 250 μg actinonin resulted in a significantly increased uptake of [ 68 Ga]Ga- 2 in the T47D tumor (5.9 ± 1.0 % ID/g (with actinonin) instead of 3.1 ± 0.9 % ID/g (without actinonin) at 2h p.i.), and an increase in tumor-to-muscle ratios from 1.8 to 4.0 upon co-administration of the inhibitor. The results impressively demonstrate the positive influence of actinonin on the in vivo stability of the NPY(Y 1 )R-specific radiopeptide [ 68 Ga]Ga- 2 , resulting in an increased tumor accumulation and improved tumor-to-background ratios. These findings thus provide important incentive for further advancement of NPY(Y 1 )R-specific tumor imaging using PET. • Peptidic NPY(Y 1 )R-specific radioligands usually exhibit a limited in vivo stability. • Structural modifications of the peptide do not sufficiently solve the problem. • Peptidase inhibitors can decelerate radiopeptide degradation. • Actinonin is a suitable inhibitor for stabilizing NPY(Y 1 )R-specific radiopeptides. • Actinonin demonstrated to decelerate radiopeptide degradation in vitro and in vivo .
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».