Synthesis, 123 I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures.

Autor:	Hasnowo LA; School of Nuclear Science and Engineering, Tomsk Polytechnic University, Tomsk 634050, Russia.; Polytechnic Institute of Nuclear Technology, National Research and Innovation Agency, Yogyakarta 55281, Indonesia., Larkina MS; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia.; Department of Pharmaceutical Analysis, Siberian State Medical University, Tomsk 634050, Russia., Plotnikov E; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia.; Mental Health Reseach Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634014, Russia., Bodenko V; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia.; Department of Pharmaceutical Analysis, Siberian State Medical University, Tomsk 634050, Russia., Yuldasheva F; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia., Stasyuk E; School of Nuclear Science and Engineering, Tomsk Polytechnic University, Tomsk 634050, Russia., Petrov SA; Department of Chemistry, M.V. Lomonosov Moscow State University Leninskie Gory, 1-3, Moscow 119991, Russia., Zyk NY; Department of Chemistry, M.V. Lomonosov Moscow State University Leninskie Gory, 1-3, Moscow 119991, Russia., Machulkin AE; Department of Chemistry, M.V. Lomonosov Moscow State University Leninskie Gory, 1-3, Moscow 119991, Russia., Vorozhtsov NI; Department of Chemistry, M.V. Lomonosov Moscow State University Leninskie Gory, 1-3, Moscow 119991, Russia., Beloglazkina EK; Department of Chemistry, M.V. Lomonosov Moscow State University Leninskie Gory, 1-3, Moscow 119991, Russia., Nenajdenko VG; Department of Chemistry, M.V. Lomonosov Moscow State University Leninskie Gory, 1-3, Moscow 119991, Russia., Tolmachev V; Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden., Orlova A; Department of Medicinal Chemistry, Uppsala University, 75183 Uppsala, Sweden., Majouga AG; Faculty of Chemistry, Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russia., Yusubov MS; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk 634050, Russia.
Jazyk:	angličtina
Zdroj:	International journal of molecular sciences [Int J Mol Sci] 2023 Jul 30; Vol. 24 (15). Date of Electronic Publication: 2023 Jul 30.
DOI:	10.3390/ijms241512206
Abstrakt:	Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [ 127 I]PSMA-m-IB and [ 127 I]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu) 3 group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of [ 123 I]PSMA-p-IB was higher than that of [ 123 I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [ 123 I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [ 123 I]PSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand [ 123 I]PSMA-p-IB showed less accumulation than [ 177 Lu]Lu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.
Databáze:	MEDLINE
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