Browse > Article
http://dx.doi.org/10.22643/JRMP.2020.6.1.3

Synthesis and in vitro evaluation of 99mTc-labeled tetraiodothyroacetic acid for tumor angiogenesis imaging  

Kim, Hyunjung (Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Koo, Hyun-Jung (Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Choe, Yearn Seong (Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Publication Information
Journal of Radiopharmaceuticals and Molecular Probes / v.6, no.1, 2020 , pp. 3-9 More about this Journal
Abstract
Tetraiodothyroacetic acid (tetrac) is a derivative of thyroid hormone T4 and causes anti-angiogenesis by blocking T4 binding to integrin αvβ3. In this study, we synthesized [99mTc]Tc-Cys-Asp-Gly(CDG)-tetrac and evaluated it in vitro as a tumor angiogenesis imaging ligand. The CDG was conjugated to tetrac as a chelator for technetium-99m labeling. The cold vial containing CDG-tetrac, sodium glucoheptonate, and reducing agent was completed under nitrogen-filled atmospheric glove bag. [99mTc]Tc-CDG-tetrac was synthesized in quantitative yield by heating the cold vial with [99mTc]TcO4- at 100℃ for 30 min. In vitro serum stability of [99mTc]Tc-CDG-tetrac was measured by incubating the radioligand in 50% fetal bovine serum at 37℃ and analyzing the incubation mixture by radio-TLC, which showed high stability over 6 h (≥ 98%). Cell binding study was carried out by incubating [99mTc]Tc-CDG-tetrac with human umbilical vein endothelial (HUVE) cells at 37℃ for 6 h. The cell binding of the radioligand increased from 100% at 0.5 h to 293.7% at 6 h in a time-dependent manner. For blocking study, the cells were incubated with the radioligand in the presence of either tetrac (20 μM) or cRGDyK (20 μM) at 37℃ for 4 h. The results demonstrated that the cell binding of the radioligand was inhibited by tetrac (19.1%) or cRGDyK (35.6%), indicating specific binding of the radioligand to integrin αvβ3. Thus, this study suggests that [99mTc]Tc-CDG-tetrac may be a potential radioligand for tumor angiogenesis imaging.
Keywords
Tetraiodothyroacetic acid (tetrac); CDG-tetrac; $^{99m}Tc$; Tumor angiogenesis;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Liu S. Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides. Adv Drug Deliv Rev 2008;60:1347-70.   DOI
2 Saha GB. Fundamentals of nuclear pharmacy. 5th ed. New York: Springer; 2004. p. 111.
3 Turaga RC, Yin L, Yang JJ, Lee H, Lvanov L, Yan C, Yang H, Grossniklaus HE, Wang S, Ma C, Sun L, Liu ZR. Rational design of a protein that binds integrin ${\alpha}_{v}{\beta}_{3}$ outside the ligand binding site. Nat Commun 2016;31:11675.
4 Zhang X, Xiong Z, Wu Y, Cai W, Tseng JR, Gambhir SS, Chen X. Quantitative PET imaging of tumor integrin ${\alpha}_{v}{\beta}_{3}$ expression with $^{18}F$-FRGD2. J Nucl Med 2006;47:113-21
5 Kim MH, Kim WH, Kim CG, Kim DW. Synthesis and evaluation of $^{99m}Tc$-labeled folate-tripeptide conjugate as a folate receptor-targeted imaging agent in a tumor-bearing mouse model. Nucl Med Mol Imaging 2015;49:200-7.   DOI
6 Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa SA, Davis PJ. Integrin ${\alpha}_{v}{\beta}_{3}$ contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 2005;146:2864-71.   DOI
7 Mousa SA, Bergh JJ, Dier E, Rebbaa A, O'Connor LJ, Yalcin M, Aljada A, Dyskin E, Davis FB, Lin HY, Davis PJ. Tetraiodothyroacetic acid, a small molecule integrin ligand, blocks angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor. Angiogenesis 2008;11:183-90.   DOI
8 Nunez R, Erwin WD, Wendt RE 3rd, Stachowiak A, Mar M, Stevens D, Madewell JE, Yeung HW, Macapinlac HA. Acquisition parameters for oncologic imaging with a new SPECT/multislice CT scanner. Mol Imaging Biol 2010;12:110-38.   DOI
9 Kang CM, Koo HJ, Lee S, Lee KC, Oh YK, Choe YS. $^{64}Cu$-Labeled tetraiodothyroacetic acid-conjugated liposomes for PET imaging of tumor angiogenesis. Nucl Med Biol 2013;40:1018-24.   DOI
10 Kim H, Koo HJ, Ahn J, Kim JY, Choi JY, Lee KH, Kim BT, Choe YS. Synthesis and characterization of $^{64}Cu$and Cy5.5-labeled tetraiodothyroacetic acid derivatives for tumor angiogenesis imaging. Bioorg Med Chem 2020;28:115212.   DOI
11 Saha GB. Fundamentals of nuclear pharmacy. 5th ed. New York: Springer; 2004. p. 97.
12 Choe YS. Radiolabeling methods used for preparation of molecular probes. Korean J Nucl Med 2004;38:121-30.
13 Leamon CP, Parker MA, Vlahov IR, Xu LC, Reddy JA, Vetzel M, Douglas N. Synthesis and biological evaluation of EC20: a new folate-derived, $^{99m}Tc$-based radiopharmaceutical. Bioconjugate Chem 2002;13:1200-10.   DOI
14 Bielenberg DR, Zetter BR. The Contribution of angiogenesis to the process of metastasis. Cancer J 2015;21:267-73.   DOI
15 Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag 2006;2:213-9.   DOI
16 Brooks PC. Role of integrins in angiogenesis. Eur J Cancer 1996;32:2423-9.   DOI
17 Jin H, Varner J. Integrins: roles in cancer development and as treatment targets. Br J Cancer 2004;90:561-5.   DOI
18 Varner JA, Cheresh DA. Integrins and cancer. Curr Opin Cell Biol 1996;8:724-30.   DOI
19 Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer 2002;2:91-100.   DOI
20 Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin ${\alpha}_{v}{\beta}_{3}$ for angiogenesis. Science 1994;264:569-71.   DOI
21 Jung KH, Lee KH, Paik JY, Ko BH, Bae JS, Lee BC, Sung HJ, Kim DH, Choe YS, Chi DY. Favorable biokinetic and tumor-targeting properties of $^{99m}Tc$-labeled glucosamino RGD and effect of Paclitaxel therapy. J Nucl Med 2006;47:2000-7.
22 Choe YS, Lee KH. Targeted in vivo imaging of angiogenesis: present status and perspectives. Curr Pharm Design 2007;13:17-31.   DOI
23 Haubner R, Wester HJ, Reuning U, Senekowitsch-Schmidtke R, Diefenbach B, Kessler H, Stocklin G, Schwaiger M. Raiolabeled ${\alpha}_{v}{\beta}_{3}$ integrin antagonists: a new class of tracers for tumor targeting. J Nucl Med 1999;40:1061-71.
24 Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, Senekowitsch-Schmidtke R, Kessler H, Schwaiger M. Noninvasive imaging of ${\alpha}_{v}{\beta}_{3}$ integrin expression using $^{18}F$-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 2001; 61:1781-5.