Copper complexes of new benzodioxotetraaza macrocycles with potential applications in nuclear medicine.
Two novel benzodioxotetraaza macrocycles [2,9-dioxo-1,4,7,10-tetraazabicyclo[10.4.0]1,11-hexadeca-1(11),13,15-triene (H2L1) and 2,10-dioxo-1,4,8,11-tetraazabicyclo[11.4.0]1,12-heptadeca-1(12),14,16-triene (H2L2)] were synthesized by a [1 + 1] crablike cyclization. The protonation constants of both ligands were determined by 1H NMR titration and by potentiometry at 25.0 degrees C in 0.10 M ionic strength in KNO3. The latter method was also used to ascertain the stability constants of their copper(II) complexes. These studies showed that the CuL1 complex has a much lower thermodynamic stability than the CuL2, and the H2L2 displays an excellent affinity for copper(II), due to the good fit of copper(II) into its cavity. The copper complexes of the novel ligands were characterized by electronic spectroscopy in solution and by crystal X-ray diffraction. These studies indicated that the copper center in the CuL1 complex adopts a square-pyramidal geometry with the four nitrogen atoms of the macrocycle forming the equatorial plane and a water molecule at axial position, and the copper in the CuL2 complex is square-planar. Several labeling conditions were tested, and only H2L2 could be labeled with 67Cu efficiently (>98%) in mild conditions (39 degrees C, 15 min) to provide a slightly hydrophilic radioligand (log D = -0.19 +/-0.03 at pH 7.4). The in vitro stability was studied in the presence of different buffers or with an excess of diethylenetriamine-pentaethanoic acid. Very high stability was shown under these conditions for over 5 days. The incubation of the radiocopper complex in human serum showed 6% protein binding.
Antunes
Patricia
P
Instituto de Tecnologia Química e Biológica, UNL, Oeiras, Portugal.
Delgado
Rita
R
Drew
Michael G B
MG
Félix
Vitor
V
Maecke
Helmut
H
D001798:Blood Proteins / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D003301:Copper Radioisotopes / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D012015:Reference Standards; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
C519942:2,10-dioxo-1,4,8,11-tetraazabicyclo(11.4.0)1,12-heptadeca-1(12),14,16-triene; C519941:2,9-dioxo-1,4,7,10-tetraazabicyclo(10.4.0)1,11-hexadeca-1(11),13,15-triene; D001798:Blood Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003301:Copper Radioisotopes; D008024:Ligands; D047028:Macrocyclic Compounds; D009942:Organometallic Compounds; D003300:Copper