Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Lutfi A. Hasnowo
ORCID logo ,
Maria S. Larkina
,
Evgenii V. Plotnikov
ORCID logo ,
Vitalina Bodenko
,
Feruza Yuldasheva
,
Elena Stasyuk
,
Stanislav A. Petrov
ORCID logo ,
Nikolai Y. Zyk
ORCID logo ,
Aleksei E. Machulkin
ORCID logo ,
Nikolay I. Vorozhtsov
,
Elena K. Beloglazkina
* ORCID logo ,
Valentine G. Nenajdenko
ORCID logo ,
Vladimir Tolmachev
ORCID logo ,
Anna Orlova
ORCID logo ,
Alexander G. Majouga
,
Mekhman S. Yusubov
Version 1 : Received: 4 July 2023 / Approved: 5 July 2023 / Online: 5 July 2023 (04:43:46 CEST)

A peer-reviewed article of this Preprint also exists.

Hasnowo, L.A.; Larkina, M.S.; Plotnikov, E.; Bodenko, V.; Yuldasheva, F.; Stasyuk, E.; Petrov, S.A.; Zyk, N.Y.; Machulkin, A.E.; Vorozhtsov, N.I.; Beloglazkina, E.K.; Nenajdenko, V.G.; Tolmachev, V.; Orlova, A.; Majouga, A.G.; Yusubov, M.S. Synthesis, 123I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures. Int. J. Mol. Sci. 2023, 24, 12206. Hasnowo, L.A.; Larkina, M.S.; Plotnikov, E.; Bodenko, V.; Yuldasheva, F.; Stasyuk, E.; Petrov, S.A.; Zyk, N.Y.; Machulkin, A.E.; Vorozhtsov, N.I.; Beloglazkina, E.K.; Nenajdenko, V.G.; Tolmachev, V.; Orlova, A.; Majouga, A.G.; Yusubov, M.S. Synthesis, 123I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures. Int. J. Mol. Sci. 2023, 24, 12206.

Abstract

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 as peptide fragment of the linker, including two phenylalanine residues in the L-configuration, and 3- or 4-(tributylstannyl)benzoic acid as 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 firstly 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 those 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 warrants further preclinical development including toxicology evaluation and experiments in tumor-bearing mice.

Keywords

DCL ligand; iodine radioisotopes; radiolabeled pharmaceuticals; targeted delivery; prostatic specific membrane antigen; prostate cancer

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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