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

Piotr Garnuszek,Justyna Pijarowska-Kruszyna,Jolanta Zaborniak,Antoni Jaroń,Wioletta Wojdowska,Urszula Karczmarczyk,Piotr F J Lipiński,Michał Maurin,Renata Mikołajczak,Arkadiusz Sikora,Monika Wyczółkowska,Dariusz Pawlak

doi:10.3390/ijms22052731

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.

Highlights

Once metastasized, prostate cancer (PCa) becomes one of the most aggressive cancer types
PSMA-617 and PSMAI&T labeled with 177 Lu are the most common in clinical use
Bearing in mind the importance of each element of a potential isotope carrier molecule, including the linker connecting the bioactive part of the drug to the radionuclide [27] in the molecular targeting of the molecule to the binding site, we have developed a new ligand for targeted radiotherapy of metastatic castration-resistant prostate cancer (mCRPC)

Summary

Introduction

Prostate cancer (PCa) becomes one of the most aggressive cancer types. The standard treatment of PCa is based on radical prostatectomy, external beam radiation therapy, or brachytherapy, chemotherapy, and hormonotherapy. These therapies are often followed by the formation of metastatic castration-resistant prostate cancer (mCRPC) [3]. The PSMA (prostate-specific membrane antigen) known as glutamate carboxypeptidase II (GCP-II) is a transmembrane, 750 amino acid, type II glycoprotein, which is expressed virtually by almost all primary prostate cancer (PCa) and metastatic disease as well [4]. Its expression increases progressively with higher-grade prostate cancer, metastatic disease, and mCRPC [14]. PSMA seems to be an ideal target for developing imaging and therapeutic radiopharmaceuticals for PCa

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