Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes

被引:430
作者
Boswell, CA
Sun, XK
Niu, WJ
Weisman, GR
Wong, EH
Rheingold, AL
Anderson, CJ
机构
[1] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA
[2] Univ Calif San Diego, Dept Chem, La Jolla, CA 92093 USA
[3] Univ New Hampshire, Dept Chem, Durham, NH 03824 USA
关键词
D O I
10.1021/jm030383m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biological molecules. The chelators most commonly utilized for labeling copper radionuclides to biomolecules are analogues of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); however, recent reports have communicated the instability of the radio-Cu(II)-TETA complexes in vivo. A class of bicyclic tetraazamacrocycles, the ethylene "crossbridged" cyclam (CB-cyclam) derivatives, form highly kinetically stable complexes with Cu(II) and therefore may be less susceptible to transchelation than their nonbridged analogues in vivo. Herein we report results on the relative biological stabilities and identification of the resulting radiolabeled metabolites of a series of Cu-64-labeled macrocyclic complexes. Metabolism studies in normal rat liver have revealed that the Cu-64 complex of 4,11-bis(carboxymethyl)1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (Cu-64-CB-TE2A) resulted in significantly lower values of protein-associated Cu-64 than Cu-64-TETA [13 +/- 6% vs 75 +/- 9% at 4 h]. A similar trend was observed for the corresponding cyclen derivatives, with the Cu-64 complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (Cu-64-CB-DO2A) undergoing less transchelation than the Cu-64 complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Cu-64-DOTA) [61 +/- 14% vs 90.3 +/- 0.5% protein associated Cu-64 at 4 h]. These data indicate that the structurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to protein in both the cyclam and cyclen cross-bridged Cu-64 complexes and that Cu-64-CB-TE2A is superior to Cu-64-CB-DO2A in that regard. These findings further suggest that a bifunctional chelator derivative of CB-TE2A is a highly desirable alternative for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.
引用
收藏
页码:1465 / 1474
页数:10
相关论文
共 56 条
[1]   Radiometal labeled agents (non-technetium) for diagnostic imaging [J].
Anderson, CJ ;
Welch, MJ .
CHEMICAL REVIEWS, 1999, 99 (09) :2219-2234
[2]  
Anderson CJ, 2001, J NUCL MED, V42, P213
[3]  
Anderson CJ, 1998, J NUCL MED, V39, P1944
[4]  
ANDERSON CJ, 1995, J NUCL MED, V36, P2315
[5]   EVALUATION OF COPPER-LABELED BIFUNCTIONAL CHELATE ALBUMIN CONJUGATES FOR BLOOD POOL IMAGING [J].
ANDERSON, CJ ;
ROCQUE, PA ;
WEINHEIMER, CJ ;
WELCH, MJ .
NUCLEAR MEDICINE AND BIOLOGY, 1993, 20 (04) :461-467
[6]   Metabolism of radiometal-labeled proteins and peptides:: What are the real radiopharmaceuticals in vivo? [J].
Anderson, CJ .
CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS, 2001, 16 (06) :451-455
[7]   Radiopharmaceuticals for targeted radiotherapy of cancer [J].
Anderson, CJ ;
Lewis, JS .
EXPERT OPINION ON THERAPEUTIC PATENTS, 2000, 10 (07) :1057-1069
[8]   Hepatobiliary transport: Molecular mechanisms of development and cholestasis [J].
Arrese, M ;
Ananthananarayanan, M ;
Suchy, FJ .
PEDIATRIC RESEARCH, 1998, 44 (02) :141-147
[9]   Synthesis and characterization of the tetraazamacrocycle 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H2Me2DO2A) and of its neutral copper(II) complex [Cu(Me2DO2A)].: A new 64Cu-labeled macrocyclic complex for positron emission tomography imaging [J].
Barbaro, P ;
Bianchini, C ;
Capannesi, G ;
Di Luca, L ;
Laschi, F ;
Petroni, D ;
Salvadori, PA ;
Vacca, A ;
Vizza, F .
JOURNAL OF THE CHEMICAL SOCIETY-DALTON TRANSACTIONS, 2000, (14) :2393-2401
[10]   How to make a metalloprotein [J].
Bartnikas, TB ;
Gitlin, JD .
NATURE STRUCTURAL BIOLOGY, 2001, 8 (09) :733-734