Copper(ii) chemistry of the functionalized macrocycle cyclam tetrapropionic acid

Abstract

The Cu(II) complex of H(4)TETP (H(4)TETP = 1,4,8,11-tetraazatetradecane-1,4,8,11-tetrapropionic acid) is five-coordinate with a distorted square-pyramidal structure (τ = 0.45; i.e. the geometry is nearly half-way between square-pyramidal and trigonal-bipyramidal) and a relatively long Cu-N and a short Cu-O bond; the comparison between powder and solution electronic spectroscopy, the frozen solution EPR spectrum and ligand-field-based calculations (angular overlap model, AOM) indicate that the solution and solid state structures are very similar, i.e. the complex has a relatively low "in-plane" and a significant axial ligand field with a d(x(2)-y(2)) ground state. The ligand-enforced structure is therefore shown to lead to a partially quenched Jahn-Teller distortion and to a relatively low complex stability, lower than with the corresponding acetate-derived ligand H(4)TETA. This is confirmed by potentiometric titration and by the biodistribution with (64)Cu-labeled ligands which show that the uptake in the liver is significantly increased with the H(4)TETP-based system.

Current advances in ligand design for inorganic positron emission tomography tracers 68Ga, 64Cu, 89Zr and 44Sc

“…131 When assessed in human serum, each ligand showed some instability with approximately 10% decomplexation occurring over 24 hours. 140 These chelates also showed a high stability to transchelation by cyclam in a competition study 140 -L 8 retained 81% of the 64 Cu after 2 hours and 30% after 24 hours when incubated with 80 equivalents of cyclen, but L 13 retained 99% even after 24 hours incubation. 131 This is likely due to the low pK a of thazole (2.80) in comparison to the imidazole units (7.00-7.10) resulting in less protonation of the thiazole at low pH values and therefore a more stable complex.…”

“…NOTThia outperformed the two imidazole based ligands when exposed to 5 M hydrochloric acidthe thiazole complex had a halflife of 55 hours at 95°C whereas the two imidazole based ligands had halflives of 30 seconds at room temperature. 140 Overall the pentadentate chelates were shown to be more stable than their tetradentate counterparts to transchelation by cyclen. All three 64 Cu complexes were retained to a degree in the kidneys of mice, with a 40% retention of 64 Cu-NOTI after 40 minutes.…”

“…In contrast the retention of the complexes in the liver is slightly lower than that of free 64 Cu 45 minutes post injection, with only 11% of NOTI being retained whereas 17% of free copper was retained. 140 These complexes also displayed very rapid radiolabelling kineticswith labelling being completed in under a minute at room temperature for L 8 -L 13 . 131 The successes seen when adapting CB-TE2A to CB-TE1A1P and CB-TE2P were not mirrored when Yoo and coworkers attempted to improve upon the radiolabelling conditions of the highly stable PCB-TE2A.…”

“…131 This is likely due to the low pK a of thazole (2.80) in comparison to the imidazole units (7.00-7.10) resulting in less protonation of the thiazole at low pH values and therefore a more stable complex. 140 In addition, the reduction of the bridging ketone to an alcohol improved the stability to transchelationit was suggested that this prevented a reverse Mannich reaction which would cause the complex to decompose. This retention was greater than that of non-chelated 64 Cu indicating that it is the complex being retained and not due to the release of the metal.…”

“…All three 64 Cu complexes were retained to a degree in the kidneys of mice, with a 40% retention of 64 Cu-NOTI after 40 minutes. 140 The stability of a number of these Cu-bispidine complexes were also tested against superoxide dismutase and in human serum. In contrast the retention of the complexes in the liver is slightly lower than that of free 64 Cu 45 minutes post injection, with only 11% of NOTI being retained whereas 17% of free copper was retained.…”