Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands

Xiankai Sun, Melinda Wuest, Gary R. Weisman, Edward H. Wong, David P. Reed, C. Andrew Boswell, Ramunas Motekaitis, Arthur E. Martell, Michael J. Welch, Carolyn J. Anderson

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chemistry. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biological molecules are analogues of TETA (1,4,8,11-tetraazacyclotetradecane1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)-TETA complexes. A new class of structurally reinforced macrocycles, the "cross-bridged" cyclam derivatives, form highly stable complexes with Cu(II) that are resistant to dissociation in strong acid. Here, we evaluate a series of 64Cu(II) cross-bridged macrocyclic complexes for biological stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-dipendant arm derivatives: 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1-4 in high radiochemical yields. The 64Cu-2 complex was neutral, while 64Cu complexes of 1, 3, and 4 were positively charged. All complexes showed no decomposition in rat serum out to 24 h. Biodistribution experiments in Sprague-Dawley rats indicated that 64Cu- 1, -3, and -4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas 64Cu-2 cleared rapidly from all tissues. The rapid clearance of the 64Cu-2 complex from the blood and liver, as well as liver metabolism experiments in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.

Original languageEnglish (US)
Pages (from-to)469-477
Number of pages9
JournalJournal of Medicinal Chemistry
Volume45
Issue number2
DOIs
StatePublished - Jan 17 2002

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Chelating Agents
Copper
Ligands
Radioisotopes
Liver
Rats
Acids
Radiopharmaceuticals
Labeling
Derivatives
Molecules
Coordination Complexes
Radiotherapy
Diagnostic Imaging
Radio
Metabolism
Edetic Acid
Sprague Dawley Rats
Blood
Experiments

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Sun, X., Wuest, M., Weisman, G. R., Wong, E. H., Reed, D. P., Boswell, C. A., ... Anderson, C. J. (2002). Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands. Journal of Medicinal Chemistry, 45(2), 469-477. https://doi.org/10.1021/jm0103817

Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands. / Sun, Xiankai; Wuest, Melinda; Weisman, Gary R.; Wong, Edward H.; Reed, David P.; Boswell, C. Andrew; Motekaitis, Ramunas; Martell, Arthur E.; Welch, Michael J.; Anderson, Carolyn J.

In: Journal of Medicinal Chemistry, Vol. 45, No. 2, 17.01.2002, p. 469-477.

Research output: Contribution to journalArticle

Sun, X, Wuest, M, Weisman, GR, Wong, EH, Reed, DP, Boswell, CA, Motekaitis, R, Martell, AE, Welch, MJ & Anderson, CJ 2002, 'Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands', Journal of Medicinal Chemistry, vol. 45, no. 2, pp. 469-477. https://doi.org/10.1021/jm0103817
Sun, Xiankai ; Wuest, Melinda ; Weisman, Gary R. ; Wong, Edward H. ; Reed, David P. ; Boswell, C. Andrew ; Motekaitis, Ramunas ; Martell, Arthur E. ; Welch, Michael J. ; Anderson, Carolyn J. / Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 2. pp. 469-477.
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T1 - Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands

AU - Sun, Xiankai

AU - Wuest, Melinda

AU - Weisman, Gary R.

AU - Wong, Edward H.

AU - Reed, David P.

AU - Boswell, C. Andrew

AU - Motekaitis, Ramunas

AU - Martell, Arthur E.

AU - Welch, Michael J.

AU - Anderson, Carolyn J.

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N2 - Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chemistry. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biological molecules are analogues of TETA (1,4,8,11-tetraazacyclotetradecane1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)-TETA complexes. A new class of structurally reinforced macrocycles, the "cross-bridged" cyclam derivatives, form highly stable complexes with Cu(II) that are resistant to dissociation in strong acid. Here, we evaluate a series of 64Cu(II) cross-bridged macrocyclic complexes for biological stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-dipendant arm derivatives: 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1-4 in high radiochemical yields. The 64Cu-2 complex was neutral, while 64Cu complexes of 1, 3, and 4 were positively charged. All complexes showed no decomposition in rat serum out to 24 h. Biodistribution experiments in Sprague-Dawley rats indicated that 64Cu- 1, -3, and -4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas 64Cu-2 cleared rapidly from all tissues. The rapid clearance of the 64Cu-2 complex from the blood and liver, as well as liver metabolism experiments in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.

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