Synthesis, Characterization and In Vivo Studies of Cu(II)-64-Labeled Cross-Bridged Tetraazamacrocycle-amide Complexes as Models of Peptide Conjugate Imaging Agents

Sprague, Jennifer; Peng, Yajun; Fiamengo, Ashley L.; Woodin, Katrina S.; Southwick, Evan; Weisman, Gary R.; Wong, Edward H.; Golen, James A.; Rheingold, Arnold L.; Anderson, Carolyn J.

doi:10.1021/jm070204r

Cited by 85 publications

(88 citation statements)

References 29 publications

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“…However, according to the reported results of the Cu-CB-TE2A (Cu (II) complex of the cross-bridged TE2A) [33], which has two trans-disubstituted carboxylate groups just like TE2A, there is very little change in the core coordination geometry around the Cu(II) ions, when one carboxylate group (carboxymethyl) of CB-TE2A was converted to an amide group (acetamido). In the X-ray crystallographic studies of CU(II)-CB-TEAMA, the amide pendant arm was found to be coordinated via the carbonyl oxygen and the distorted octahedral coordination geometry is maintained, as in the Cu-CB-TE2A complex [34]. The biodistribution studies also showed the good in vivo stability of the 64 Cu-crossbridged monoamides, supporting the hypothesis that CB-TE2A is able to be used as a BFC without any structural modifications of the macrocycle backbone [35].…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Hexaazamacrobicyclic cage-type ligands, based upon the sepulchrate or sarcophagine cage motifs, have been efficiently radiolabeled under mild conditions and have been shown to possess high in vivo stability ( Figure 1). 4,20,21 However, the yield of antibody conjugation with these chelators is often low because of side reactions including protein cross-linking caused by the use of 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC). 22 Moreover, copper complexes of these ligands carry a net positive charge, which leads to high hepatic uptake and slow kidney clearance.…”

Section: ■ Introductionmentioning

confidence: 99%

“…22 Moreover, copper complexes of these ligands carry a net positive charge, which leads to high hepatic uptake and slow kidney clearance. 23−25 Derivatives of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) 26,27 and cross-bridged 4,11-bis-(carboxymethyl)-1,4,8,11-tetraaza-bicyclo[6.6.2]hexadecane (CB-TE2A) 19,20 form negative or neutral complexes with Cu(II) and demonstrate high in vivo stability ( Figure 1). In fact, the latter forms one of the most stable complexes with 64 Cu(II) 28 and the Cu(II)-CB-TE2A complex is more resistant to the reductive metal loss than any other known tetramacrocyclic complexes.…”

Section: ■ Introductionmentioning

confidence: 99%

Click-Chemistry Strategy for Labeling Antibodies with Copper-64 via a Cross-Bridged Tetraazamacrocyclic Chelator Scaffold

et al. 2015

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We report a click-chemistry based modular strategy for antibody labeling with (64)Cu (t1/2 = 12.7 h; β(+) 0.656 MeV, 17.4%; β(-) 0.573 MeV, 39%; EC 43%) under ambient condition utilizing a cross-bridged tetraazamacrocyclic (CB-TE2A) analogue, which otherwise requires harsh conditions that make the CB-TE2A analogues under-utilized for protein labeling despite the fact that they form kinetically inert copper complexes with high in vivo stability. Our strategy involves prelabeling a CB-TE2A based scaffold (CB-TE2A-1C) with (64)Cu and its subsequent reaction with an antibody via the tetrazine-norbornene mediated click chemistry. The effectiveness of this strategy was demonstrated by labeling two monoclonal antibodies, an anti-PSMA antibody (YPSMA-1) and a chimeric anti-phosphatidylserine antibody (Bavituximab). The immunoreactivity of the antibodies remained unchanged after the tetrazine modification and click-chemistry (64)Cu labeling. To further demonstrate the practicality of the modular (64)Cu labeling strategy, we tested positron emission tomography (PET) imaging of tumor with the (64)Cu-labeled bavituximab in a mouse xenograft model. The tumor visualization and uptake of the labeled antibody exhibited the versatility of the click-chemistry strategy.

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“…28 Cross-bridged monoamides, model compounds of peptide-conjugated ECB-TE2A, showed high in vivo stability and fast body clearance. 29 On the basis of high structural similarity between ECB-TE2A and DM-TE2A, high in vivo stability of 64 Cu-radiolabeled DM-TE2A-bioconjugate is also expected. However, all further conjugation using MM/ DM-TE2A and following in vivo stability of conjugates should be evaluated by appropriate experiments.…”

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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Synthesis, Characterization and In Vivo Studies of Cu(II)-64-Labeled Cross-Bridged Tetraazamacrocycle-amide Complexes as Models of Peptide Conjugate Imaging Agents

Cited by 85 publications

References 29 publications

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

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

Click-Chemistry Strategy for Labeling Antibodies with Copper-64 via a Cross-Bridged Tetraazamacrocyclic Chelator Scaffold

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

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Synthesis, Characterization and In Vivo Studies of Cu(II)-64-Labeled Cross-Bridged Tetraazamacrocycle-amide Complexes as Models of Peptide Conjugate Imaging Agents

Cited by 85 publications

References 29 publications

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

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

Click-Chemistry Strategy for Labeling Antibodies with Copper-64 via a Cross-Bridged Tetraazamacrocyclic Chelator Scaffold

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

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