Synthesis, 123I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures; International Journal of Molecular Sciences; Vol. 24, iss. 15
| Parent link: | International Journal of Molecular Sciences.— .— Basel: MDPI AG Vol. 24, iss. 15.— 2023.— Article number 12206, 30 p. |
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| Other Authors: | , , , , , , , , , |
| Summary: | Title screen 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 [127I]PSMA-m-IB and [127I]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 [123I]PSMA-p-IB was higher than that of [123I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [123I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [123I]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 [123I]PSMA-p-IB showed less accumulation than [177Lu]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 Текстовый файл |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | http://earchive.tpu.ru/handle/11683/132514 https://doi.org/10.3390/ijms241512206 |
| Format: | Electronic Book Chapter |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=680375 |
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| 200 | 1 | |a Synthesis, 123I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures |f Lutfi A. Hasnowo, Maria S. Larkina, Evgenii Plotnikov [et al.] | |
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| 330 | |a 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 [127I]PSMA-m-IB and [127I]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 [123I]PSMA-p-IB was higher than that of [123I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [123I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [123I]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 [123I]PSMA-p-IB showed less accumulation than [177Lu]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 | ||
| 336 | |a Текстовый файл | ||
| 461 | 1 | |t International Journal of Molecular Sciences |c Basel |n MDPI AG | |
| 463 | 1 | |t Vol. 24, iss. 15 |v Article number 12206, 30 p. |d 2023 | |
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| 610 | 1 | |a труды учёных ТПУ | |
| 610 | 1 | |a DCL ligand | |
| 610 | 1 | |a iodine radioisotopes | |
| 610 | 1 | |a radiolabeled pharmaceuticals | |
| 610 | 1 | |a targeted delivery | |
| 610 | 1 | |a prostate-specific membrane antigen | |
| 610 | 1 | |a prostate cancer | |
| 701 | 1 | |a Khasnovo |b L. A. |g Lutfi Aditjya | |
| 701 | 1 | |a Larkina |b M. S. |g Mariya Sergeevna |f 1984- |c pharmacist |c Professor; Senior Researcher of the Tomsk Polytechnic University, Doctor of Pharmaceutical Sciences |9 22417 | |
| 701 | 1 | |a Plotnikov |b E. V. |c chemist |c Associate Professor of Tomsk Polytechnic University, Candidate of Chemical Sciences |f 1983- |g Evgeny Vladimirovich |9 16417 | |
| 701 | 1 | |a Bodenko |b V. V. |c pharmacist |c engineer at Tomsk Polytechnic University |f 1997- |g Vitalina Vasiljevna |9 88553 | |
| 701 | 1 | |a Yuldasheva |b F. Sh. |g Feruza Sherzod kizi | |
| 701 | 1 | |a Stasyuk (Stasiuk) |b E. S. |c Specialist in the field of nuclear power engineering |c Researcher of Tomsk Polytechnic University, Candidate of technical sciences |f 1978- |g Elena Sergeyevna |9 16555 | |
| 701 | 1 | |a Petrov |b S. |g Stanislav | |
| 701 | 1 | |a Zyk |b N. |g Nikolai | |
| 701 | 1 | |a Machulkin |b A. |g Aleksei | |
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