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Article

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,^† and Carolyn J. Anderson*^†

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824-3598, and Department of Chemistry, Texas A&M University, College Station, Texas 77843

J. Med. Chem., 2002, 45 (2), pp 469–477

DOI: 10.1021/jm0103817

Publication Date (Web): December 19, 2001

†

Washington University School of Medicine.

‡

University of New Hampshire.

Texas A&M University.

Deceased.

Author to whom correspondence should be addressed. Tel: (314)362-8427. Fax: (314)362-9940. E-mail: AndersonCJ@mir.wustl.edu.

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-tetraazacyclotetradecane-1,4,8,11-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-di-pendant 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.