1. Development of a new class of PSMA radioligands comprising ibuprofen as an albumin-binding entity
- Author
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Christoph A. Umbricht, Martina Benešová, Roger Schibli, Konstantin Zhernosekov, Cristina Müller, Francesca Borgna, Luisa M. Deberle, and Manuel Büchler
- Subjects
Glutamate Carboxypeptidase II ,Male ,Medicine (miscellaneous) ,Ibuprofen ,Lutetium ,Pharmacology ,Ligands ,urologic and male genital diseases ,030218 nuclear medicine & medical imaging ,Mice ,0302 clinical medicine ,Radioligand ,Tissue Distribution ,prostate cancer ,PSMA ligands ,Lu-177 ,albumin-binder ,ibuprofen ,Internalization ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,media_common ,chemistry.chemical_classification ,Chemistry ,In vitro toxicology ,3. Good health ,Amino acid ,Prostatic Neoplasms, Castration-Resistant ,030220 oncology & carcinogenesis ,Antigens, Surface ,Female ,Serum Globulins ,Research Paper ,Biodistribution ,Single Photon Emission Computed Tomography Computed Tomography ,Injections, Subcutaneous ,media_common.quotation_subject ,Mice, Nude ,Serum Albumin, Human ,03 medical and health sciences ,Pharmacokinetics ,Albumins ,Cell Line, Tumor ,Animals ,Humans ,Cyclooxygenase Inhibitors ,Radioisotopes ,Albumin ,177Lu ,Xenograft Model Antitumor Assays ,In vitro ,Radiopharmaceuticals ,Carrier Proteins - Abstract
Prostate-specific membrane antigen (PSMA)-targeted radioligands have been used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently, albumin-binding PSMA radioligands with enhanced blood circulation were developed to increase the tumor accumulation of activity. The present study aimed at the design, synthesis and preclinical evaluation of a novel class of PSMA-targeting radioligands equipped with ibuprofen as a weak albumin-binding entity in order to improve the pharmacokinetic properties. Methods: Four novel glutamate-urea-based PSMA ligands were synthesized with ibuprofen, conjugated via variable amino acid-based linker entities. The albumin-binding properties of the 177Lu-labeled PSMA ligands were tested in vitro using mouse and human plasma. Affinity of the radioligands to PSMA and cellular uptake and internalization was investigated using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor cells. The tissue distribution profile of the radioligands was assessed in biodistribution and imaging studies using PC-3 PIP/flu tumor-bearing nude mice. Results: The PSMA ligands were obtained in moderate yields at high purity (>99%). 177Lu-labeling of the ligands was achieved at up to 100 MBq/nmol with >96% radiochemical purity. In vitro assays confirmed high binding of all radioligands to mouse and human plasma proteins and specific uptake and internalization into PSMA-positive PC-3 PIP tumor cells. Biodistribution studies and SPECT/CT scans revealed high accumulation in PC-3 PIP tumors but negligible uptake in PC-3 flu tumor xenografts as well as rapid clearance of activity from background organs and tissues. 177Lu-Ibu-DAB-PSMA, in which ibuprofen was conjugated via a positively-charged diaminobutyric acid (DAB) entity, showed distinguished tumor uptake and the most favorable tumor-to-blood and tumor-to-kidney ratios. Conclusion: The high accumulation of activity in the tumor and fast clearance from background organs was a common favorable characteristic of PSMA radioligands modified with ibuprofen as albumin-binding entity. 177Lu-Ibu-DAB-PSMA emerged as the most promising candidate; hence, more detailed preclinical investigations with this radioligand are warranted in view of a clinical translation. ISSN:1838-7640
- Published
- 2020