PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties.

Abstract

A new PSMA ligand (PSMA-D4) containing the Glu-CO-Lys pharmacophore connected with a new linker system (L-Trp-4-Amc) and chelator DOTA was developed for radiolabeling with therapeutic radionuclides. Herein we describe the synthesis, radiolabeling, and preliminary biological evaluation of the novel PSMA-D4 ligand. Synthesized PSMA-D4 was characterized using TOF-ESI-MS, NMR, and HPLC methods. The novel compound was subject to molecular modeling with GCP-II to compare its binding mode to analogous reference compounds. The radiolabeling efficiency of PSMA-D4 with 177Lu, 90Y, 47Sc, and 225Ac was chromatographically tested. In vitro studies were carried out in PSMA-positive LNCaP tumor cells membranes. The ex vivo tissue distribution profile of the radioligands and Cerenkov luminescence imaging (CLI) was studied in LNCaP tumor-bearing mice. PSMA-D4 was synthesized in 24% yield and purity >97%. The radio complexes were obtained with high yields (>97%) and molar activity ranging from 0.11 to 17.2 GBq mcmol-1, depending on the radionuclide. In vitro assays confirmed high specific binding and affinity for all radiocomplexes. Biodistribution and imaging studies revealed high accumulation in LNCaP tumor xenografts and rapid clearance of radiocomplexes from blood and non-target tissues. These render PSMA-D4 a promising ligand for targeted therapy of prostate cancer (PCa) metastases.

• Authors: Piotr Garnuszek, Urszula Karczmarczyk, Michał Maurin, Arkadiusz Sikora, Jolanta Zaborniak, Justyna Pijarowska-Kruszyna, Antoni Jaroń, Monika Wyczółkowska, Wioletta Wojdowska, Dariusz Pawlak, Piotr F J Lipiński, Renata Mikołajczak
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 5 (Mar 08 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33800517 (Publication Type: Journal Article)

Chemical References

• Radiopharmaceuticals
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen

Topics

• Animals
• Drug Delivery Systems
• Humans
• Kallikreins (chemistry, pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• PC-3 Cells
• Prostate-Specific Antigen (chemistry, pharmacology)
• Prostatic Neoplasms (metabolism, pathology, radiotherapy)
• Radiopharmaceuticals (chemical synthesis, chemistry, pharmacology)
• Xenograft Model Antitumor Assays