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A New Synthesis of TE2A-a Potential Bifunctional Chelator for $^{64}Cu$
Pandya, Darpan N.,Kim, Jung Young,Kwak, Won-Jung,Park, Jeong-Chan,Gawande, Manoj B.,An, Gwang-Il,Ryu, Eun-Kyoung,Yoo, Jeong-Soo The Korea Society of Nuclear Medicine 2010 핵의학 분자영상 Vol.44 No.3
Purpose The development of a new bifunctional chelator, which holds radiometals strongly in living systems, is a prerequisite for the successful application of diseasespecific biomolecules to medical diagnosis and therapy. Recently, TE2A was reported to make kinetically more stable Cu(II) complexes than TETA. Herein, we report a new synthetic route to TE2A and explore its potential as a bifunctional chelator. Methods TE2A was synthesized using the regioselective alkylation of benzyl bromoacetate and successive deprotection of the methylene bridge and benzyl group. Salt-free TE2A was radiolabeled with $^{64}Cu$ and microPET imaging was performed to follow the clearance pattern of the $^{64}Cu$-TE2A complex. TE2A was conjugated with cyclic RGD peptide and the TE2A-c(RGDyK) conjugate was radiolabeled with $^{64}Cu$. Results TE2A was prepared in salt-free form from cyclam in an overall yield of 74%. The microPET images showed that $^{64}Cu$-TE2A is excreted rapidly from the body by the kidney and liver. TE2A was successfully conjugated with c(RGDyK) peptide through one carboxylate group and the TE2A-c(RGDyK) conjugate was radiolabeled with $^{64}Cu$ in 94% yield within 30 min. Conclusion TE2A can be used by itself as a bifunctional chelator without any further structural modification.
Revival of TE2A; a better chelate for Cu(II) ions than TETA?
Pandya, Darpan N.,Kim, Jung Young,Park, Jeong Chan,Lee, Hochun,Phapale, Prasad B.,Kwak, Wonjung,Choi, Tae Hyun,Cheon, Gi Jeong,Yoon, Young-Ran,Yoo, Jeongsoo Royal Society of Chemistry 2010 Chemical communications Vol.46 No.20
<P>A highly effective synthetic route for TE2A was developed and the <SUP>64</SUP>Cu-labeled TE2A complexes showed higher kinetic inertness and faster clearance than most commonly used TETA analogs.</P> <P>Graphic Abstract</P><P>A facile synthetic route for TE2A was developed and TE2A was found to make a more kinetically stable Cu(II) complex than TETA. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=b925703a'> </P>
Pandya, Darpan N.,Bhatt, Nikunj,An, Gwang Il,Ha, Yeong Su,Soni, Nisarg,Lee, Hochun,Lee, Yong Jin,Kim, Jung Young,Lee, Woonghee,Ahn, Heesu,Yoo, Jeongsoo American Chemical Society 2014 Journal of medicinal chemistry Vol.57 No.17
<P>The first macrocyclic bifunctional chelator incorporating propylene cross-bridge was efficiently synthesized from cyclam in seven steps. After the introduction of an extra functional group for facile conjugation onto the propylene cross-bridge, the two carboxylic acid pendants could contribute to strong coordination of Cu(II) ions, leading to a robust Cu complex. The cyclic RGD peptide conjugate of PCB-TE2A-NCS was prepared and successfully radiolabeled with <SUP>64</SUP>Cu ion. The radiolabeled peptide conjugate was evaluated in vivo through a biodistribution study and animal PET imaging to demonstrate high tumor uptake with low background.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2014/jmcmar.2014.57.issue-17/jm500348z/production/images/medium/jm-2014-00348z_0011.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm500348z'>ACS Electronic Supporting Info</A></P>
New macrobicyclic chelator for the development of ultrastable 64Cu-radiolabeled bioconjugate.
Pandya, Darpan N,Dale, Ajit V,Kim, Jung Young,Lee, Hochun,Ha, Yeong Su,An, Gwang Il,Yoo, Jeongsoo American Chemical Society 2012 Bioconjugate chemistry Vol.23 No.3
<P>Ethylene cross-bridged cyclam with two acetate pendant arms, ECB-TE2A, is known to form the most kinetically stable (64)Cu complexes. However, its usefulness as a bifunctional chelator is limited because of its harsh radiolabeling conditions. Herein, we report new cross-bridged cyclam chelator for the development of ultrastable (64)Cu-radiolabeled bioconjugates. Propylene cross-bridged TE2A (PCB-TE2A) was successfully synthesized in an efficient way. The Cu(II) complex of PCB-TE2A exhibited much higher kinetic stability than ECB-TE2A in acid decomplexation studies, and also showed high resistance to reduction-mediated demetalation. Furthermore, the quantitative radiolabeling of PCB-TE2A with (64)Cu was achieved under milder conditions compared to ECB-TE2A. Biodistribution studies strongly indicate that the (64)Cu complexes of PCB-TE2A cleared out rapidly from the body with minimum decomplexation.</P>
Dale, Ajit V.,An, Gwang Il,Pandya, Darpan N.,Ha, Yeong Su,Bhatt, Nikunj,Soni, Nisarg,Lee, Hochun,Ahn, Heesu,Sarkar, Swarbhanu,Lee, Woonghee,Huynh, Phuong Tu,Kim, Jung Young,Gwon, Mi-Ri,Kim, Sung Hong American Chemical Society 2015 Inorganic Chemistry Vol.54 No.17
<P>Bifunctional chelators have been successfully used to construct Cu-64-labeled radiopharmaceuticals. Previously reported chelators with cross-bridged cyclam backbones have various essential features such as high stability of the copper(II) complex, high efficiency of radiolabeling at room temperature, and good biological inertness of the radiolabeled complex, along with rapid body clearance. Here, we report a new generation propylene-cross-bridged chelator with hybrid acetate/phosphonate pendant groups (PCB-TE1A1P) developed with the aim of combining these key properties in a single chelator. The PCB-TE1A1P was synthesized from cyclam with good overall yield. The Cu(II) complex of our chelator showed good robustness in kinetic stability evaluation experiments, such as acidic decomplexation and cyclic voltammetry studies. The Cu(II) complex of PCB-TE1A1P remained intact under highly acidic conditions (12 M HC1, 90 degrees C) for 8 d and showed quasi-reversible reduction/oxidation peaks at -0.77 V in electrochemical studies. PCB-TE1A1P was successfully radiolabeled with Cu-66 ions in an acetate buffer at 60 degrees C within 60 min. The electrophoresis study revealed that the Cu-64-PCB-TE1A1P complex has net negative charge in aqueous solution. The biodistribution and in vivo stability study profiles of 64Cu-PCB-TE1A1P indicated that the radioactive complex was stable under physiological conditions and cleared rapidly from the body. A whole body positron emission tomography (PET) imaging study further confirmed high in vivo stability and fast clearance of the complex in mouse models. In conclusion, PCB-TE1A1P has good potential as a bifunctional chelator for 'Cu-based radiopharmaceuticals, especially those involving peptides.</P>
Visualization and Quantification of Radiochemical Purity by Cerenkov Luminescence Imaging
Ha, Yeong Su,Lee, Woonghee,Jung, Jung-Min,Soni, Nisarg,Pandya, Darpan N.,An, Gwang Il,Sarkar, Swarbhanu,Lee, Won Kee,Yoo, Jeongsoo American Chemical Society 2018 ANALYTICAL CHEMISTRY - Vol.90 No.15
<P>Determination of radiochemical purity is essential for characterization of all radioactive compounds, including clinical radiopharmaceuticals. Radio-thin layer chromatography (radio-TLC) has been used as the gold standard for measurement of radiochemical purity; however, this method has several limitations in terms of sensitivity, spatial resolution, two-dimensional scanning, and quantification accuracy. Here, we report a new analytical technique for determination of radiochemical purity based on Cerenkov luminescence imaging (CLI), whereby entire TLC plates are visualized by detection of Cerenkov radiation. Sixteen routinely used TLC plates were tested in combination with three different radioisotopes (<SUP>131</SUP>I, <SUP>124</SUP>I, and <SUP>32</SUP>P). All TLC plates doped with a fluorescent indicator showed excellent detection sensitivity with scanning times of less than 1 min. The new CLI method was superior to the traditional radio-TLC scanning method in terms of sensitivity, scanning time, spatial resolution, and two-dimensional scanning. The CLI method also showed better quantification features across a wider range of radioactivity values compared with radio-TLC and classical zonal analysis, especially for β<SUP>-</SUP>-emitters such as <SUP>131</SUP>I and <SUP>32</SUP>P.</P> [FIG OMISSION]</BR>
Sarkar, Swarbhanu,Bhatt, Nikunj,Ha, Yeong Su,Huynh, Phuong Tu,Soni, Nisarg,Lee, Woonghee,Lee, Yong Jin,Kim, Jung Young,Pandya, Darpan N.,An, Gwang Il,Lee, Kyo Chul,Chang, Yongmin,Yoo, Jeongsoo American Chemical Society 2018 Journal of medicinal chemistry Vol.61 No.1
<P>Although the importance of bifunctional chelators (BFCs) is well recognized, the chemophysical parameters of chelators that govern the biological behavior of the corresponding bioconjugates have not been clearly elucidated. Here, five BFCs closely related in structure were conjugated with a cyclic RGD peptide and radiolabeled with Cu-64 ions. Various biophysical and chemical properties of the Cu(II) complexes were analyzed with the aim of identifying correlations between individual factors and the biological behavior of the conjugates. Tumor uptake and body clearance of the <SUP>64</SUP>Cu-labeled bioconjugates were directly compared by animal PET imaging in animal models, which was further supported by biodistribution studies. Conjugates containing propylene cross-bridged chelators showed higher tumor uptake, while a closely related ethylene cross-bridged analogue exhibited rapid body clearance. High in vivo stability of the copper–chelator complex was strongly correlated with high tumor uptake, while the overall lipophilicity of the bioconjugate affected both tumor uptake and body clearance.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2018/jmcmar.2018.61.issue-1/acs.jmedchem.7b01671/production/images/medium/jm-2017-016718_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm7b01671'>ACS Electronic Supporting Info</A></P>