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; Kwak, Wonjung; Choi, Tae Hyun; Cheon, Gi Jeong; Yoon, Young‐Ran; Yoo, Jeongsoo

doi:10.1039/b925703a

Cited by 53 publications

(76 citation statements)

References 22 publications

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“…Even though we had difficulties in quantifying the remaining activity in kidney and liver at 24 h postinjection because of blurred outline of the organs in microPET images, the time activity curve analysis at 1 and 4 h clearly suggests that 64 Cu-TE2A complexes are cleared out mainly via renal route instead of hepatobilliary system. The percent injected dose per gram values in kidney and liver at 24 h (0.052 and 0.057, respectively) calculated from microPET images are comparable with the corresponding data in the biodistribution studies (0.139 and 0.073%ID/g, respectively) [25].…”

Section: Discussionsupporting

confidence: 81%

“…In the following step, the benzyl group was easily removed by simple hydrogenation to afford TE2A in salt-free form in high yield (Scheme 1). Compared with our recent, novel method of synthesizing TE2A [25], the current one seems to be less effective, because the total number of synthesis steps from the cyclam is four versus three in the previous one and the overall yield is also slightly lower (74 vs 86%). However, as mentioned above, the final compound, TE2A, could be obtained in salt-free form using this method.…”

Section: Discussionmentioning

confidence: 66%

“…However, to the best of our knowledge, no further papers on TE2A have since been published. Quite recently, we reported a new facile method of synthesizing TE2A [25]. We used a bisaminal compound to make the regioselective transdisubstituted cyclam and were able to prepare a derivative of compound 2 using t-butyl bromoacetate in 95% yield, and then deprotected both the t-butyl group and methylene bridge in one step to yield TE2A in the hydrochloride salt form.…”

Section: Discussionmentioning

confidence: 99%

“…Very recently, we found that TE2A (1,8-N,N′-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane) forms more kinetically stable Cu(II) complexes than TETA and reported the great potential of TE2A as a BFC [25]. However, the conjugation of TE2A with the amino group of biomolecules does not seem to be straightforward, because it has only two carboxylate groups and, upon conjugation, one of the two carboxylate pendants would be converted to an amide and its binding ability as a ligand would therefore be compromised.…”

Section: Introductionmentioning

confidence: 99%

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A New Synthesis of TE2A—a Potential Bifunctional Chelator for 64Cu

Pandya

Kim

Kwak

et al. 2010

Nucl Med Mol Imaging

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A New Synthesis of TE2A—a Potential Bifunctional Chelator for 64Cu

Pandya

Kim

Kwak

et al. 2010

Nucl Med Mol Imaging

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“…14,15 We have reported that TE2A (1,8-N,N′-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane) is a better chelator for Cu(II) ions than TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) and DOTA (1,4,7,10-tetraazacyclodo-decane-1,4,7,10-tetraacetic acid) in terms of high kinetic stability and easy radiolabeling. 16 TE2A forms a stable Cu(II) complex by attaining a strong N 4 in-plane ligand field in the trans configuration, whereas the Cu-TETA complex prefers N 2 O 2 coordination in an equatorial plane, even in the same trans configuration. 17−19 Here, we report the synthesis and physical characterization of N-dimethyl TE2A (DM-TE2A), which is a structural analogue of ECB-TE2A with a broken ethylene cross-bridge.…”

mentioning

confidence: 99%

Non-Cross-Bridged Tetraazamacrocyclic Chelator for Stable ⁶⁴Cu-Based Radiopharmaceuticals

Dale

Pandya

Kim

et al. 2013

ACS Med. Chem. Lett.

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N-mono/dimethylated TE2A tetraazamacrocycles (MM-TE2A and DM-TE2A) were synthesized in high yields. Both Cu-MM/DM-TE2A complexes showed increased kinetic stability compared to that of Cu-TE2A, whereas Cu-DM-TE2A showed even higher in vitro stability than that of Cu-ECB-TE2A. MM-TE2A and DM-TE2A were quantitatively radiolabeled with 64 Cu ions and showed rapid clearance from the body to emerge as a potential efficient bifunctional chelator. KEYWORDS: Bifunctional chelator, copper complex, imaging agent, radiopharmaceutical A dvances in metal-based radiopharmaceuticals are driving research and development for medical diagnosis and therapy. 1−3 Several copper radioisotopes ( 60 Cu, 61 Cu, 62 Cu, 64 Cu, and 67 Cu) have attractive physical properties for medical applications, and various radioactive copper labeled bioconjugates are in the clinical trial pipeline. 4−6 The successful development of Cu(II)-based radiopharmaceuticals is not only dependent on targeting biomolecules but also highly dependent on the proper choice of a bifunctional chelator (BFC) coordinating radioactive Cu(II) ions. 7−9 Enormous efforts to construct an ideal BFC have been seen in recent decades. These BFCs should be radiolabeled with radioactive copper ions at a mild temperature with fast reaction kinetics, form stable complex with Cu(II), and possess rapid body clearance.Various tetraazamacrocyclic BFCs containing N-acetic acid pendant arms have been utilized for Cu(II) complexation (Figure 1). The kinetic stability of BFC-Cu(II) complexes could indicate their in vivo stability more closely than thermodynamic stability. 10 The order of stability for the BFC-Cu(II) complexes is Cu-ECB-TE2A ≫ Cu-TETA ≈ Cu-DOTA > Cu-EDTA. 10,11 It is now well accepted that 64 Cu-TETA and 64 Cu-DOTA are prone to transchelation of 64 Cu ions to proteins under physiological conditions resulting in slow body clearance of radioactivity. 12,13 Ethylene cross-bridged (ECB)-TE2A shows excellent kinetic stability for Cu(II) ions in acid decomplexation experiments and equally good in vivo inertness. However, despite this high stability, ECB-TE2A suffers from shortcomings such as cumbersome synthesis (total synthesis time: 35 days and 45% overall yield from cyclam), and harsh radiolabeling conditions for 64 Cu ions (1−2 h at 75−95°C). 14, 15 We have reported that TE2A (1,8-N,N′-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane) is a better chelator for Cu(II) ions than TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) and DOTA (1,4,7,10-tetraazacyclodo-

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Electroreductive Decomplexation and Isomerism of Copper(II) Complexes with Cyclam Ligands for Medical Use

Koláčná,

Maďar,

Kubíček

et al. 2024

ChemElectroChem

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Detailed electrochemical study of copper(II) complexes of cyclam bearing two phosphonate (TE2P), phenolate (TE2PhOH) or carboxylate (TE2A) pendant arms (together with one cross‐bridged‐cyclam derivative cb‐TE2A) was performed using cyclic voltammetry (CV) and polarography. The electrochemical‐heterogeneous measurements were accompanied by UV‐vis spectra describing the situation in homogeneous phase. Reduction of complexes on mercury electrode in buffered aqueous solutions (pH 2–12) occurs generally as a two‐electron process of reductive decomposition. The formed Cu‐amalgam can be (e. g. during the anodic scan of CV) reoxidized to Cu(II) cation which undergoes re‐complexation resulting in the original complex. This process of a square diagram is manifold repeatable. The results also showed presence of several isomers differing in mutual orientation of substituents on cyclam nitrogen atoms. The primary “kinetic”, pentacoordinated isomers are irreversibly transformed to the stable, hexacoordinated “thermodynamic” ones upon heating. The development of isomerization process was followed electrochemically. The cross‐bridged cb‐TE2A derivative forms only one isomer which does not change even after heating. The higher stability of the complex manifests itself at pH>8 when the complex is reversibly reduced in one‐electron step, formally CuII/CuI, without decomposition.

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Revival of TE2A; a better chelate for Cu(II) ions than TETA?

Abstract: A highly effective synthetic route for TE2A was developed and the (64)Cu-labeled TE2A complexes showed higher kinetic inertness and faster clearance than most commonly used TETA analogs.

Cited by 53 publications

References 22 publications

A New Synthesis of TE2A—a Potential Bifunctional Chelator for 64Cu

A New Synthesis of TE2A—a Potential Bifunctional Chelator for 64Cu

Non-Cross-Bridged Tetraazamacrocyclic Chelator for Stable ⁶⁴Cu-Based Radiopharmaceuticals

Electroreductive Decomplexation and Isomerism of Copper(II) Complexes with Cyclam Ligands for Medical Use

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Revival of TE2A; a better chelate for Cu(II) ions than TETA?

Abstract: A highly effective synthetic route for TE2A was developed and the (64)Cu-labeled TE2A complexes showed higher kinetic inertness and faster clearance than most commonly used TETA analogs.

Cited by 53 publications

References 22 publications

A New Synthesis of TE2A—a Potential Bifunctional Chelator for 64Cu

A New Synthesis of TE2A—a Potential Bifunctional Chelator for 64Cu

Non-Cross-Bridged Tetraazamacrocyclic Chelator for Stable 64Cu-Based Radiopharmaceuticals

Electroreductive Decomplexation and Isomerism of Copper(II) Complexes with Cyclam Ligands for Medical Use

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Non-Cross-Bridged Tetraazamacrocyclic Chelator for Stable ⁶⁴Cu-Based Radiopharmaceuticals