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:	Hanane Lahnif, Tilmann Grus, Stefanie Pektor, Lukas Greifenstein, Mathias Schreckenberger, Frank Rösch
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	prostate specific membrane antigen PSMA hybrid chelator radionuclide diagnosis and therapy Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/a9eb4683b79f4443a8fc6edd6be9f631
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spelling	oai:doaj.org-article:a9eb4683b79f4443a8fc6edd6be9f6312021-11-11T18:22:04ZHybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach10.3390/molecules262163321420-3049https://doaj.org/article/a9eb4683b79f4443a8fc6edd6be9f6312021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6332https://doaj.org/toc/1420-3049(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<sup>5m</sup>.SA.KuE and AAZTA<sup>5</sup>.SA.KuE were synthesized. DATA<sup>5m</sup>.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 <i>in vitro</i> assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated <i>in vivo</i> and <i>ex vivo</i> using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA<sup>5m</sup>.SA.KuE was synthesized successfully. AAZTA<sup>5</sup>.SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA<sup>5m</sup>.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. [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA<sup>5</sup>.SA.KuE and DATA<sup>5m</sup>.SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. <i>In vivo</i> and <i>ex vivo</i> studies of [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>.SA.KuE, [<sup>44</sup>Sc]Sc-AAZTA<sup>5</sup>.SA.KuE and [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>.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 <i>in vivo</i> allowing for translational theranostic use.Hanane LahnifTilmann GrusStefanie PektorLukas GreifensteinMathias SchreckenbergerFrank RöschMDPI AGarticleprostate specific membrane antigen PSMAhybrid chelatorradionuclide diagnosis and therapyOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6332, p 6332 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	prostate specific membrane antigen PSMA hybrid chelator radionuclide diagnosis and therapy Organic chemistry QD241-441
spellingShingle	prostate specific membrane antigen PSMA hybrid chelator radionuclide diagnosis and therapy Organic chemistry QD241-441 Hanane Lahnif Tilmann Grus Stefanie Pektor Lukas Greifenstein Mathias Schreckenberger Frank Rösch Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
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<sup>5m</sup>.SA.KuE and AAZTA<sup>5</sup>.SA.KuE were synthesized. DATA<sup>5m</sup>.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 <i>in vitro</i> assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated <i>in vivo</i> and <i>ex vivo</i> using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA<sup>5m</sup>.SA.KuE was synthesized successfully. AAZTA<sup>5</sup>.SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA<sup>5m</sup>.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. [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA<sup>5</sup>.SA.KuE and DATA<sup>5m</sup>.SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. <i>In vivo</i> and <i>ex vivo</i> studies of [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>.SA.KuE, [<sup>44</sup>Sc]Sc-AAZTA<sup>5</sup>.SA.KuE and [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>.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 <i>in vivo</i> allowing for translational theranostic use.
format	article
author	Hanane Lahnif Tilmann Grus Stefanie Pektor Lukas Greifenstein Mathias Schreckenberger Frank Rösch
author_facet	Hanane Lahnif Tilmann Grus Stefanie Pektor Lukas Greifenstein Mathias Schreckenberger Frank Rösch
author_sort	Hanane Lahnif
title	Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
title_short	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_sort	hybrid chelator-based psma radiopharmaceuticals: translational approach
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a9eb4683b79f4443a8fc6edd6be9f631
work_keys_str_mv	AT hananelahnif hybridchelatorbasedpsmaradiopharmaceuticalstranslationalapproach AT tilmanngrus hybridchelatorbasedpsmaradiopharmaceuticalstranslationalapproach AT stefaniepektor hybridchelatorbasedpsmaradiopharmaceuticalstranslationalapproach AT lukasgreifenstein hybridchelatorbasedpsmaradiopharmaceuticalstranslationalapproach AT mathiasschreckenberger hybridchelatorbasedpsmaradiopharmaceuticalstranslationalapproach AT frankrosch hybridchelatorbasedpsmaradiopharmaceuticalstranslationalapproach
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Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach

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