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Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach

(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new co...

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Autores principales: Lahnif, Hanane, Grus, Tilmann, Pektor, Stefanie, Greifenstein, Lukas, Schreckenberger, Mathias, Rösch, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588462/
https://www.ncbi.nlm.nih.gov/pubmed/34770742
http://dx.doi.org/10.3390/molecules26216332
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author Lahnif, Hanane
Grus, Tilmann
Pektor, Stefanie
Greifenstein, Lukas
Schreckenberger, Mathias
Rösch, Frank
author_facet Lahnif, Hanane
Grus, Tilmann
Pektor, Stefanie
Greifenstein, Lukas
Schreckenberger, Mathias
Rösch, Frank
author_sort Lahnif, Hanane
collection PubMed
description (1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA(5m).SA.KuE and AAZTA(5).SA.KuE were synthesized. DATA(5m).SA.KuE was labeled with gallium-68 and radiochemical yields of various amounts of precursor at different temperatures were determined. Complex stability in phosphate-buffered saline (PBS) and human serum (HS) was examined at 37 °C. Binding affinity and internalization ratio were determined in in vitro assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated in vivo and ex vivo using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA(5m).SA.KuE was synthesized successfully. AAZTA(5).SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA(5m).SA.KuE with gallium-68 was performed in ammonium acetate buffer (1 M, pH 5.5). High radiochemical yields (>98%) were obtained with 5 nmol at 70 °C, 15 nmol at 50 °C, and 60 nmol (50 µg) at room temperature. [(68)Ga]Ga-DATA(5m).SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA(5).SA.KuE and DATA(5m).SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. In vivo and ex vivo studies of [(177)Lu]Lu-AAZTA(5).SA.KuE, [(44)Sc]Sc-AAZTA(5).SA.KuE and [(68)Ga]Ga-DATA(5m).SA.KuE displayed specific accumulation in the tumor along with fast clearance and reduced off-target uptake. (4) Conclusions: Both KuE-conjugates showed promising properties especially in vivo allowing for translational theranostic use.
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spelling pubmed-85884622021-11-13 Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach Lahnif, Hanane Grus, Tilmann Pektor, Stefanie Greifenstein, Lukas Schreckenberger, Mathias Rösch, Frank Molecules Article (1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA(5m).SA.KuE and AAZTA(5).SA.KuE were synthesized. DATA(5m).SA.KuE was labeled with gallium-68 and radiochemical yields of various amounts of precursor at different temperatures were determined. Complex stability in phosphate-buffered saline (PBS) and human serum (HS) was examined at 37 °C. Binding affinity and internalization ratio were determined in in vitro assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated in vivo and ex vivo using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA(5m).SA.KuE was synthesized successfully. AAZTA(5).SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA(5m).SA.KuE with gallium-68 was performed in ammonium acetate buffer (1 M, pH 5.5). High radiochemical yields (>98%) were obtained with 5 nmol at 70 °C, 15 nmol at 50 °C, and 60 nmol (50 µg) at room temperature. [(68)Ga]Ga-DATA(5m).SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA(5).SA.KuE and DATA(5m).SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. In vivo and ex vivo studies of [(177)Lu]Lu-AAZTA(5).SA.KuE, [(44)Sc]Sc-AAZTA(5).SA.KuE and [(68)Ga]Ga-DATA(5m).SA.KuE displayed specific accumulation in the tumor along with fast clearance and reduced off-target uptake. (4) Conclusions: Both KuE-conjugates showed promising properties especially in vivo allowing for translational theranostic use. MDPI 2021-10-20 /pmc/articles/PMC8588462/ /pubmed/34770742 http://dx.doi.org/10.3390/molecules26216332 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lahnif, Hanane
Grus, Tilmann
Pektor, Stefanie
Greifenstein, Lukas
Schreckenberger, Mathias
Rösch, Frank
Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
title Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
title_full Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
title_fullStr Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
title_full_unstemmed Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
title_short Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
title_sort hybrid chelator-based psma radiopharmaceuticals: translational approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588462/
https://www.ncbi.nlm.nih.gov/pubmed/34770742
http://dx.doi.org/10.3390/molecules26216332
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