Novel Cationic 99mTc Complexes for Heart Imaging

Summary

Principal Investigator: Shuang Liu
Abstract: Myocardial perfusion imaging with radionuclides is an integral component of the clinical evaluation of patients with known or suspected coronary artery disease (CAD) in current clinical practice. 99mTc has been the isotope of choice for the development of myocardial perfusion imaging agents because of its ideal nuclear properties (half-life and gamma-energy) and its diverse coordination chemistry. The use of 99mTc allows simultaneous assessment of myocardial perfusion and cardiac function in a single study. Since early 1980s, extensive research efforts have been directed towards the development of lipophilic Tc complex cations as heart imaging agent. As a result of these efforts, 99mTc-sestamibi and 99mTc-Tetrofosmin have been approved as commercial products for myocardial imaging. Despite their widespread use in clinic, they do not meet the requirements of an ideal perfusion agent at least partially due to their low first-pass extraction and high background activity in liver and lungs. Thus, there is a continuing need for better 99mTc radiopharmaceuticals for myocardial perfusion imaging. This project provides novel crown ether-containing cationic 99mTc-nitrido complex radiopharmaceuticals useful for heart imaging. The new radiopharmaceuticals that will be prepared and evaluated in the present project are based upon very promising results from our preliminary studies. These new cationic 99mTc-nitrido complexes are composed of a [99TcN]2+ core, a crown ether-containing dithiocarbamate (crowned DTC) and a triphosphine coligand. This project will use the cationic character for initial heart uptake of the cationic 99mTc-nitrido complex. Once the complex is able to enter the cell, the crown ether group may interact with intracellular K+ and form highly charged 99mTc species, which are not able to easily move out of the cell. The unique combination of cationic character with the presence of crown ether groups may result in cationic 99mTc-nitrido complexes that are substantially better than 99mTc-Sestamibi and 99mTc-Tetrofosmin. The goal of this research is to provide the proof-of-principle for the proposed cationic 99mTc-nitrido complexes. Accordingly, the SPECIFIC AIMS are: 1. Synthesis and characterization of cationic 99mTc-nitrido complexes. 2. Biological evaluation of cationic 99mTc-nitrido complexes in Sprague-Dawley rats. 3. Biological evaluation of selected cationic 99mTc-nitrido complexes in male Harley guinea pigs. 4. Structural characterization of cationic Re-nitrido complexes. If they show high heart uptake and favorable kinetics in both rat and guinea pig models, they would more likely to have a high heart uptake in humans. Once the basic principle is established, we will conduct more extensive SAR studies to explore the effect of alkoxyalkyl substituents of the triphosphine coliaands on biological properties (heart uptake and excretion kinetics) in the future. Our long-term goal is to develop new Tc complex radiopharmaceuticals for myocardial perfusion imaging. Successful development of new 99mTc perfusion imaging agents will have a profound impact on diagnostic evaluation, risk stratification, and therapeutic decision-making in patients with CAD.
Funding Period: 2005-08-01 - 2008-07-31
more information: NIH RePORT

Top Publications

  1. pmc Improving tumor uptake and pharmacokinetics of (64)Cu-labeled cyclic RGD peptide dimers with Gly(3) and PEG(4) linkers
    Jiyun Shi
    Purdue University, West Lafayette, Indiana 47907, USA
    Bioconjug Chem 20:750-9. 2009
  2. ncbi 99mTc-labeling of HYNIC-conjugated cyclic RGDfK dimer and tetramer using EDDA as coligand
    Jianjun Wang
    School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907, USA
    Bioconjug Chem 19:634-42. 2008
  3. ncbi Synthesis and characterization of a novel macrocyclic chelator with 3-hydroxy-4-pyrone chelating arms and its complexes with medicinally important metals
    Chang Tong Yang
    School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, Indiana 47907, USA
    Inorg Chem 47:2719-27. 2008
  4. ncbi Effects of targeting moiety, linker, bifunctional chelator, and molecular charge on biological properties of 64Cu-labeled triphenylphosphonium cations
    Young Seung Kim
    School of Health Sciences, Purdue University, West Lafayette, IN, USA
    J Med Chem 51:2971-84. 2008
  5. ncbi Tc-99m-N-MPO: novel cationic Tc-99m radiotracer for myocardial perfusion imaging
    Young Seung Kim
    School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
    J Nucl Cardiol 15:535-46. 2008
  6. ncbi Evaluation of 99mTcN-15C5 as a new myocardial perfusion imaging agent in normal dogs and canines with coronary stenosis
    Wei Fang
    Department of Nuclear Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Science and Peking Union Medical College Beijing, China
    Nucl Med Commun 29:775-81. 2008
  7. pmc 64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium cations as highly selective tumor imaging agents: effects of linkers and chelates on radiotracer biodistribution characteristics
    Chang Tong Yang
    School of Health Sciences, Purdue University, West Lafayette, Indiana, USA
    Bioconjug Chem 19:2008-22. 2008
  8. pmc Improving tumor-targeting capability and pharmacokinetics of (99m)Tc-labeled cyclic RGD dimers with PEG(4) linkers
    Lijun Wang
    School of Health Sciences, Purdue University, Indiana 47907, USA
    Mol Pharm 6:231-45. 2009
  9. pmc Evaluation of (64)Cu(DO3A-xy-TPEP) as a potential PET radiotracer for monitoring tumor multidrug resistance
    Shuang Liu
    Purdue University, West Lafayette, Indiana
    Bioconjug Chem 20:790-8. 2009
  10. ncbi Mechanism for myocardial localization and rapid liver clearance of Tc-99m-N-MPO: a new perfusion radiotracer for heart imaging
    Young Seung Kim
    School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
    J Nucl Cardiol 16:571-9. 2009

Scientific Experts

  • Shuang Liu
  • Young Seung Kim
  • Chang Tong Yang
  • Jianjun Wang
  • Jiyun Shi
  • Zhengjie He
  • Wen Yuan Hsieh
  • Xiaoyuan Chen
  • Lijun Wang
  • Shizhen Zhai
  • Zhaofei Liu
  • Bing Jia
  • Zi Bo Li
  • Fan Wang
  • Huiyun Zhao
  • Wei Fang
  • Subramanya G Sreerama
  • Guihua Hou
  • Alexis Broisat
  • Zhi Yang
  • Zuo Xiang He
  • Yajing Liu
  • Jian Jian Li
  • Lin Zhu
  • David K Glover
  • Ming Fan
  • Zilin Yu
  • Yongxin Li
  • Qizhen Cao

Detail Information

Publications22

  1. pmc Improving tumor uptake and pharmacokinetics of (64)Cu-labeled cyclic RGD peptide dimers with Gly(3) and PEG(4) linkers
    Jiyun Shi
    Purdue University, West Lafayette, Indiana 47907, USA
    Bioconjug Chem 20:750-9. 2009
    ..MicroPET imaging data clearly demonstrate the utility of (64)Cu(DOTA-3G(3)-dimer) as a new PET radiotracer for imaging integrin alpha(v)beta(3)-positive tumors...
  2. ncbi 99mTc-labeling of HYNIC-conjugated cyclic RGDfK dimer and tetramer using EDDA as coligand
    Jianjun Wang
    School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907, USA
    Bioconjug Chem 19:634-42. 2008
    ..It was also found that the radiotracer tumor uptake decreases in a linear fashion as the tumor size increases. The smaller the tumors are, the higher the tumor uptake is regardless of the identity of radiotracer...
  3. ncbi Synthesis and characterization of a novel macrocyclic chelator with 3-hydroxy-4-pyrone chelating arms and its complexes with medicinally important metals
    Chang Tong Yang
    School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, Indiana 47907, USA
    Inorg Chem 47:2719-27. 2008
    ....
  4. ncbi Effects of targeting moiety, linker, bifunctional chelator, and molecular charge on biological properties of 64Cu-labeled triphenylphosphonium cations
    Young Seung Kim
    School of Health Sciences, Purdue University, West Lafayette, IN, USA
    J Med Chem 51:2971-84. 2008
    ..Considering the tumor uptake and tumor/liver ratios, 64Cu(DO2A-xy-TPP)+ is the best candidate for more extensive evaluations in different tumor-bearing animal models...
  5. ncbi Tc-99m-N-MPO: novel cationic Tc-99m radiotracer for myocardial perfusion imaging
    Young Seung Kim
    School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
    J Nucl Cardiol 15:535-46. 2008
    ..Technetium 99m-N-MPO ([Tc-99m-N(mpo)(PNP5)](+)) is a cationic Tc-99m nitrido complex. The objective of this study is to evaluate its potential as a new radiotracer for myocardial perfusion imaging...
  6. ncbi Evaluation of 99mTcN-15C5 as a new myocardial perfusion imaging agent in normal dogs and canines with coronary stenosis
    Wei Fang
    Department of Nuclear Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Science and Peking Union Medical College Beijing, China
    Nucl Med Commun 29:775-81. 2008
    ..This study was designed to evaluate the biodistribution and blood clearance characteristics of 99mTcN-15C5 and its potential as a myocardial perfusion radiotracer...
  7. pmc 64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium cations as highly selective tumor imaging agents: effects of linkers and chelates on radiotracer biodistribution characteristics
    Chang Tong Yang
    School of Health Sciences, Purdue University, West Lafayette, Indiana, USA
    Bioconjug Chem 19:2008-22. 2008
    ..Considering both tumor uptake and T/B ratios (particularly tumor/heart, tumor/liver, and tumor/muscle), it was concluded that (64)Cu(DO3A-xy-TPEP) is a promising PET radiotracer for imaging the MDR-negative tumors...
  8. pmc Improving tumor-targeting capability and pharmacokinetics of (99m)Tc-labeled cyclic RGD dimers with PEG(4) linkers
    Lijun Wang
    School of Health Sciences, Purdue University, Indiana 47907, USA
    Mol Pharm 6:231-45. 2009
    ..Thus, (99m)Tc-3PEG(4)-dimer is a very promising radiotracer for the early detection of integrin alpha(v)beta(3)-positive tumors, and may have the potential for noninvasive monitoring of tumor growth or treatment efficacy...
  9. pmc Evaluation of (64)Cu(DO3A-xy-TPEP) as a potential PET radiotracer for monitoring tumor multidrug resistance
    Shuang Liu
    Purdue University, West Lafayette, Indiana
    Bioconjug Chem 20:790-8. 2009
    ..Thus, it is reasonable to believe that (64)Cu(DO3A-xy-TPEP), like (99m)Tc-Sestamibi, is able to localize in mitochondria due to the increased plasma and mitochondrial transmembrane potentials in tumor cells...
  10. ncbi Mechanism for myocardial localization and rapid liver clearance of Tc-99m-N-MPO: a new perfusion radiotracer for heart imaging
    Young Seung Kim
    School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
    J Nucl Cardiol 16:571-9. 2009
    ..The main objective of this study is to elucidate the mechanism for myocardial localization and fast liver clearance of Tc-99m-N-MPO in comparison with Tc-99m-sestamibi ([Tc-99m-(MIBI)(6)](+): MIBI = 2-methoxy-2-methylpropylisonitrile)...
  11. pmc Coligand effects on the solution stability, biodistribution and metabolism of the (99m)Tc-labeled cyclic RGDfK tetramer
    Shuang Liu
    School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
    Nucl Med Biol 35:111-21. 2008
    ..Among the three radiotracers evaluated in this tumor-bearing animal model, [(99m)Tc(HYNIC tetramer)(tricine)(TPPTS)] remained the best with respect to blood clearance, tumor uptake and target/background ratios...
  12. pmc Linker effects on biological properties of 111In-labeled DTPA conjugates of a cyclic RGDfK dimer
    Bing Jia
    Medical Isotopes Research Center, Peking University, Beijing 100083, China
    Bioconjug Chem 19:201-10. 2008
    ..It is concluded that using a glutamic acid linker can significantly improve excretion kinetics of the 111 In-labeled E[c(RGDfK)] 2 from liver and kidneys...
  13. pmc A novel ternary ligand system useful for preparation of cationic (99m)Tc-diazenido complexes and (99m)Tc-labeling of small biomolecules
    Young Seung Kim
    Department of Industrial and Physical Pharmaceuticals, Division of Nuclear Pharmacy, Purdue University, 575 Stadium Drive, West Lafayette, Indiana 147907 205, USA
    Bioconjug Chem 17:473-84. 2006
    ..However, the (99m)Tc-labeling efficiency of HYBA is much lower than that of 6-hydrazinonicotinic acid (HYNIC) with tricine and trisodium triphenylphosphine-3,3',3''-trisulfonate (TPPTS) as coligands...
  14. ncbi Evaluation of novel cationic (99m)Tc-nitrido complexes as radiopharmaceuticals for heart imaging: improving liver clearance with crown ether groups
    Shuang Liu
    School of Health Sciences, Purdue University, Lafayette, IN 47907, USA
    Nucl Med Biol 33:419-32. 2006
    ..99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ are very promising candidates for further evaluation in more extensive preclinical animal models...
  15. pmc Novel biscapped and monocapped tris(dioxime) Mn(II) complexes: x-ray crystal structure of the first cationic tris(dioxime) Mn(II) complex [Mn(CDOH)3BPh]OH (CDOH2= 1,2-cyclohexanedione dioxime)
    Wen Yuan Hsieh
    Department of Industrial and Physical Pharmacy, School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, Indiana 47907, USA
    Inorg Chem 45:5034-43. 2006
    ....
  16. pmc Impact of PKM linkers on biodistribution characteristics of the 99mTc-labeled cyclic RGDfK dimer
    Shuang Liu
    School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, Indiana 47907, USA
    Bioconjug Chem 17:1499-507. 2006
    ..E and K may have advantages over PEG4 due to a combination of relatively low liver uptake and high tumor/liver and tumor/lung ratios of ternary ligand complexes [99mTc(HYNIC-PKM-SU016)(tricine)(TPPTS)] (PKM = E and K)...
  17. ncbi Evaluation of novel cationic 99mTc(I)-tricarbonyl complexes as potential radiotracers for myocardial perfusion imaging
    Zhengjie He
    School of Health Sciences, Purdue University, West Lafayette, IN 47907 2051, USA
    Nucl Med Biol 33:1045-53. 2006
    ..99m)Tc(CO)(3)(15C5-PNP)](+) is a very promising candidate for more preclinical evaluations in various animal models...
  18. pmc Impact of bidentate chelators on lipophilicity, stability, and biodistribution characteristics of cationic 99mTc-nitrido complexes
    Young Seung Kim
    Civil Engineering Building, School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, Indiana 47907, USA
    Bioconjug Chem 18:929-36. 2007
    ..99mTcN(etma)(PNP5)](+) is a very promising candidate for more preclinical evaluations in various animal models...
  19. pmc Synthesis and structural characterization of complexes of a DO3A-conjugated triphenylphosphonium cation with diagnostically important metal ions
    Chang Tong Yang
    School of Health Sciences, Purdue University, West Lafayette, Indiana 47907, USA
    Inorg Chem 46:8988-97. 2007
    ..There is no dissociation of the acetate chelating arms in In(DO3A-xy-TPP)+ and Ga(DO3A-xy-TPP)+, providing indirect evidence for the high solution stability of (111)In(DO3A-xy-TPP)+ and (68)Ga(DO3A-xy-TPP)+...
  20. ncbi 64Cu-Labeled triphenylphosphonium and triphenylarsonium cations as highly tumor-selective imaging agents
    Jianjun Wang
    School of Health Sciences, Purdue University, West Lafayette, Indiana, USA
    J Med Chem 50:5057-69. 2007
    ..The 64Cu-labeled TPP/TPA cations are very selective radiotracers that are able to provide the information of mitochondrial bioenergetic function in tumors by monitoring mitochondrial potential in a noninvasive fashion...
  21. ncbi Effect of coligands on biodistribution characteristics of ternary ligand 99mTc complexes of a HYNIC-conjugated cyclic RGDfK dimer
    Shuang Liu
    Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, USA
    Bioconjug Chem 16:1580-8. 2005
    ..On the basis of their liver uptake and tumor/liver ratios, we believe that PDA has the advantage over TPPTS and ISONIC for the (99m)Tc-labeling of HYNIC-biomolecule conjugates...