Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach

Hanane Lahnif; Tilmann Grus; Stefanie Pektor; Lukas Greifenstein; Mathias Schreckenberger; Frank Rösch

doi:10.3390/molecules26216332

Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach

Molecules. 2021 Oct 20;26(21):6332. doi: 10.3390/molecules26216332.

Authors

Hanane Lahnif¹, Tilmann Grus¹, Stefanie Pektor², Lukas Greifenstein^{1

3}, Mathias Schreckenberger², Frank Rösch¹

Affiliations

¹ Department of Chemistry-TRIGA Site, Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
² Department of Nuclear Medicine, University Medical Center Mainz, 55131 Mainz, Germany.
³ Curanosticum Wiesbaden-Frankfurt, 65191 Wiesbaden, Germany.

Abstract

(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 AAZTA⁵.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. AAZTA⁵.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. [⁶⁸Ga]Ga-DATA^5m.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA⁵.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 [¹⁷⁷Lu]Lu-AAZTA⁵.SA.KuE, [⁴⁴Sc]Sc-AAZTA⁵.SA.KuE and [⁶⁸Ga]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.

Keywords: hybrid chelator; prostate specific membrane antigen PSMA; radionuclide diagnosis and therapy.

MeSH terms

Animals
Antigens, Surface / chemistry*
Chelating Agents / chemical synthesis
Chelating Agents / chemistry*
Chemistry Techniques, Synthetic
Diagnostic Imaging / methods
Disease Models, Animal
Glutamate Carboxypeptidase II / antagonists & inhibitors
Glutamate Carboxypeptidase II / chemistry*
Heterografts
Humans
Isotope Labeling
Kinetics
Mice
Molecular Structure
Neoplasms / diagnostic imaging
Neoplasms / etiology
Protein Binding
Radiopharmaceuticals / chemical synthesis
Radiopharmaceuticals / chemistry*
Translational Research, Biomedical

Substances

Antigens, Surface
Chelating Agents
Radiopharmaceuticals
FOLH1 protein, human
Glutamate Carboxypeptidase II