What a difference a methylene makes: replacing Glu with Asp or Aad in the Lys-urea-Glu pharmacophore of PSMA-targeting radioligands to reduce kidney and salivary gland uptake
Notice bibliographique
Résumé
The aim of this study was to investigate the effect of replacing Glu in the Lys-urea-Glu PSMA-targeting pharmacophore of [ 68 Ga]Ga-HTK03041 with a close analog on the uptake of kidneys, salivary glands and PSMA-expressing tumor xenografts.Methods: HTK03161, HTK03149 and HTK03189A/B were obtained by replacing Glu in HTK03041 with Asp, Aad (L-2-aminoadipic acid) and Api (2-aminopimelic acid), respectively.PSMA binding affinities were measured by competition binding assays.PET imaging and biodistribution studies of 68 Ga-labeled ligands were performed in LNCaP tumor-bearing mice.The best candidate HTK03149 was selected and radiolabeled with 177 Lu, and SPECT imaging and biodistribution studies were performed in LNCaP tumor-bearing mice.Radiation dosimetry calculation was conducted using the OLINDA software.Radioligand therapy study was performed in LNCaP tumor-bearing mice treated with [ 177 Lu]Lu-HTK03149 (9.3-148 MBq), [ 177 Lu]Lu-PSMA-617 (37 MBq) or nat Lu-HTK03149 (500 pmol).Results: PSMA binding affinities (Ki) of Ga-HTK03161, Ga-HTK03149, Ga-HTK03189A and Lu-HTK03149 were 3.88±0.66,6.99±0.80,550±35.7 and 1.57±0.42nM, respectively.PET imaging showed that all 68 Ga-labeled HTK03161, HTK03149 and HTK03189A/B were excreted mainly via the renal pathway and had minimal uptake in all organs/tissues including kidneys and salivary glands.Tumor xenografts were clearly visualized in PET images of [ 68 Ga]Ga-HTK03161 and [ 68 Ga]Ga-HTK03149 but were barely visualized using [ 68 Ga]Ga-HTK03189A/B.Tumor uptake values for [ 68 Ga]Ga-HTK03161, [ 68 Ga]Ga-HTK03149, [ 68 Ga]Ga-HTK0189A and [ 68 Ga]Ga-HTK03189B were 12.7±1.91,19.1±6.37,2.10±0.28 and 0.67±0.15%IA/g, respectively at 1h post-injection, and their average kidney and salivary gland uptake values were 2.13-4.41 and 0.20-0.23 %IA/g, respectively.Longitudinal SPECT imaging studies showed that [ 177 Lu]Lu-HTK03149 was excreted mainly through the renal pathway with high uptake in LNCaP tumors and minimal uptake in all normal organs/tissues.The tumor uptake of [ 177 Lu]Lu-HTK03149 peaked at 4h post-injection (20.9±2.99 %IA/g) and the uptake was sustained over time.Compared to [ 177 Lu]Lu-PSMA-617, [ 177 Lu]Lu-HTK03149 had 145% increase in tumor absorbed dose but 70% less in kidney absorbed dose, leading to an 7.1-fold increase in tumor-to-kidney absorbed dose ratio.Radioligand therapy studies showed that only half of the [ 177 Lu]Lu-PSMA-617 injected dosage was needed for [ 177 Lu]Lu-HTK03149 to achieve the same median survival.Conclusion: Replacing Glu in the PSMA-targeting Lys-urea-Glu pharmacophore of [ 68 Ga]Ga-HTK03041 with Asp and Aad generates [ 68 Ga]Ga-HTK03161 and [ 68 Ga]Ga-HTK03149, respectively, and the new derivatives retain high uptake in LNCaP tumors and have minimal uptake in normal organs/tissues including kidneys and salivary glands.[ 177 Lu]Lu-HTK03149 also retain high uptake in LNCaP tumors and has minimal uptake in normal organs/tissues, and is, therefore, promising for clinical translation to treat prostate cancer.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».