Radiolabeling and Biological Evaluation of Novel Tc-Nitrido and Tc-Oxo Complexes with 4-Methoxy--Phenylalanine Dithiocarbamate for Tumor Imaging

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2022 Oct 27

PMID 36297631

Authors

Guangxing Yin

Qing Ruan

Yuhao Jiang

Junbo Zhang

Affiliations

Soon will be listed here.

Abstract

To develop novel radiolabeled amino acid tumor imaging agents, 4-methoxy-L-phenylalanine dithiocarbamate (MOPADTC) was synthesized successfully, and two kinds of 99mTc-labeled complexes ([99mTc]TcN-MOPADTC and [99mTc]TcO-MOPADTC) with high radiochemical purities (RCP > 95%) were obtained. The in vitro stability and partition coefficient were determined, and the results show that both of these complexes have good in vitro stability; [99mTc]TcO-MOPADTC is hydrophilic, while [99mTc]TcN-MOPADTC is slightly lipophilic. The biodistribution of [99mTc]TcN-MOPADTC and [99mTc]TcO-MOPADTC in mice bearing S180 tumors shows that the tumor uptake and tumor/muscle ratio of [99mTc]TcO-MOPADTC were higher than the tumor uptake and tumor/muscle ratio of [99mTc]TcN-MOPADTC. In addition, the tumor retention of [99mTc]TcO-MOPADTC is better than the tumor retention of [99mTc]TcN-MOPADTC. A competitive inhibition assay was performed, and the results indicate that [99mTc]TcO-MOPADTC may enter cells primarily via the L-alanine/L-serine/L-cysteine (ASC) system. Single-photon emission computed tomography (SPECT) imaging of [99mTc]TcO-MOPADTC shows obvious accumulation in tumor sites, suggesting that [99mTc]TcO-MOPADTC is a novel potential tumor-imaging agent.

References

McConathy J, Yu W, Jarkas N, Seo W, Schuster D, Goodman M . Radiohalogenated nonnatural amino acids as PET and SPECT tumor imaging agents. Med Res Rev. 2011; 32(4):868-905. DOI: 10.1002/med.20250. View

Zhang S, Zhang W, Wang Y, Jin Z, Wang X, Zhang J . Synthesis and biodistribution of a novel (⁹⁹m)TcN complex of norfloxacin dithiocarbamate as a potential agent for bacterial infection imaging. Bioconjug Chem. 2011; 22(3):369-75. DOI: 10.1021/bc100357w. View

Chang J, Lee H, Goo J, Lee H, Lee J, Chung J . False positive and false negative FDG-PET scans in various thoracic diseases. Korean J Radiol. 2006; 7(1):57-69. PMC: 2667579. DOI: 10.3348/kjr.2006.7.1.57. View

Van den Wyngaert T, Elvas F, De Schepper S, Kennedy J, Israel O . SPECT/CT: Standing on the Shoulders of Giants, It Is Time to Reach for the Sky!. J Nucl Med. 2020; 61(9):1284-1291. DOI: 10.2967/jnumed.119.236943. View

Zhu J, Song X, Zhang J . Development of Amino Acid-Based Radiopharmaceuticals for Tumor Imaging. Mini Rev Med Chem. 2016; 18(7):561-583. DOI: 10.2174/1389557516666160428115446. View

Closs E, Boissel J, Habermeier A, Rotmann A . Structure and function of cationic amino acid transporters (CATs). J Membr Biol. 2007; 213(2):67-77. DOI: 10.1007/s00232-006-0875-7. View

Williams S, Flores-Mercado J, Port R, Bengtsson T . Quantitation of glucose uptake in tumors by dynamic FDG-PET has less glucose bias and lower variability when adjusted for partial saturation of glucose transport. EJNMMI Res. 2012; 2:6. PMC: 3395842. DOI: 10.1186/2191-219X-2-6. View

Kaim A, Weber B, Kurrer M, Westera G, Schweitzer A, Gottschalk J . (18)F-FDG and (18)F-FET uptake in experimental soft tissue infection. Eur J Nucl Med Mol Imaging. 2002; 29(5):648-54. DOI: 10.1007/s00259-002-0780-y. View

Carolina do A H de Souza A, Harms H, Martell L, Bibbo C, Harrington M, Sullivan K . Accuracy and Reproducibility of Myocardial Blood Flow Quantification by Single Photon Emission Computed Tomography Imaging in Patients With Known or Suspected Coronary Artery Disease. Circ Cardiovasc Imaging. 2022; 15(6):e013987. PMC: 9233115. DOI: 10.1161/CIRCIMAGING.122.013987. View

10.

Bouhlel A, Zhou D, Li A, Yuan L, Rich K, McConathy J . Synthesis, Radiolabeling, and Biological Evaluation of (R)- and (S)-2-Amino-5-[(18)F]fluoro-2-methylpentanoic Acid ((R)-, (S)-[(18)F]FAMPe) as Potential Positron Emission Tomography Tracers for Brain Tumors. J Med Chem. 2015; 58(9):3817-29. PMC: 4476065. DOI: 10.1021/jm502023y. View

11.

Hyde R, Taylor P, Hundal H . Amino acid transporters: roles in amino acid sensing and signalling in animal cells. Biochem J. 2003; 373(Pt 1):1-18. PMC: 1223487. DOI: 10.1042/bj20030405. View

12.

Wu R, Liu S, Liu Y, Sun Y, Cheng X, Huang Y . Synthesis and biological evaluation of [F](2S,4S)4-(3-fluoropropyl) arginine as a tumor imaging agent. Eur J Med Chem. 2019; 183:111730. DOI: 10.1016/j.ejmech.2019.111730. View

13.

Blower P, Singh J, Clarke S . The chemical identity of pentavalent technetium-99m-dimercaptosuccinic acid. J Nucl Med. 1991; 32(5):845-9. View

14.

Boellaard R, Delgado-Bolton R, Oyen W, Giammarile F, Tatsch K, Eschner W . FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging. 2014; 42(2):328-54. PMC: 4315529. DOI: 10.1007/s00259-014-2961-x. View

15.

Kong F, Zhang Y, Ali M, Oh C, Mendez R, Kohanim S . Synthesis of (99m)Tc-EC-AMT as an imaging probe for amino acid transporter systems in breast cancer. Nucl Med Commun. 2010; 31(8):699-707. DOI: 10.1097/MNM.0b013e328339ea48. View

16.

Siddiq I, Atwa S, Shama S, Eltaoudy M, Omar W . Radiosynthesis and modified quality control of O-(2-[F]fluoroethyl)-L-tyrosine ([F]FET) for brain tumor imaging. Appl Radiat Isot. 2017; 133:38-44. DOI: 10.1016/j.apradiso.2017.12.011. View

17.

Chen J, Li C, Hong H, Liu H, Wang C, Xu M . Side Chain Optimization Remarkably Enhances the in Vivo Stability of F-Labeled Glutamine for Tumor Imaging. Mol Pharm. 2019; 16(12):5035-5041. DOI: 10.1021/acs.molpharmaceut.9b00891. View

18.

Rosenbaum S, Lind T, Antoch G, Bockisch A . False-positive FDG PET uptake--the role of PET/CT. Eur Radiol. 2005; 16(5):1054-65. DOI: 10.1007/s00330-005-0088-y. View

19.

McGivan J, Pastor-Anglada M . Regulatory and molecular aspects of mammalian amino acid transport. Biochem J. 1994; 299 ( Pt 2):321-34. PMC: 1138275. DOI: 10.1042/bj2990321. View

20.

Huang C, McConathy J . Radiolabeled amino acids for oncologic imaging. J Nucl Med. 2013; 54(7):1007-10. DOI: 10.2967/jnumed.112.113100. View