Stable and inert macrocyclic cobalt(II) and nickel(II) complexes with paraCEST response

We report the synthesis of the macrocyclic ligands 3,9 PC2AMH (2,2’-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,9-diyl)diacetamide) and 3,9-PC2AMtBu (2,2’-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,9-diyl)bis(N-tert-butyl)acetamide) which contain a pyclen platform functionalized with acetamide or tert-butylacetamide pendant arms at positions 3 and...

Metal–ligand interactions in complexes of cyclen-based ligands with Bi and Ac

The structural and bonding properties of Bi and Ac complexes with cyclen-based chelating ligands have been studied using relativistic DFT calculations in conjunction with TZ2P all-electron basis sets. Besides the parent cyclen ligand, the study has covered its extensions with pyridine-type (Lpy), carboxylate (DOTA, DOTPA), picolinate (MeDO2PA) and phosphonate (DOTMP) pendant arms. The effect of the cyclen ring size has been probed by increasing it from [12]aneN4 to [16]aneN4. Additional extensions in the DOTA complexes included the H2O ligand at the 9th coordination site as well as the p-SCN-Bn substituent (a popular linker to the targeting vector). The study focuses on the complex stability, the nature of bonding and the differences between Ac and Bi in the complexes. The metal–ligand interactions have been analysed by the Extended Transition State method combined with Natural Orbitals of Chemical Valence theory and Quantum Theory of Atoms in Molecules models.

Benzothiazole Carboxylate Diester Bifunctional Chelators for 64Cu PET Imaging in Alzheimer’s Disease

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid β aggregates, strong binding affinity towards Cu(II), and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate ester pendant arms enable high binding affinity towards Cu(II). The BFCs form stable ⁶⁴Cu-radiolabeled complexes and exhibit favorable partition coefficient (log D) values of 0.75-0.95. Among the five compounds tested, the <b>⁶⁴Cu-YW-1</b> and <b>⁶⁴Cu-YW-13</b> complexes exhibit significant staining of amyloid plaques in <i>ex vivo</i> autoradiography studies.

Benzothiazole Carboxylate Diester Bifunctional Chelators for 64Cu PET Imaging in Alzheimer’s Disease

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid β aggregates, strong binding affinity towards Cu(II), and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate ester pendant arms enable high binding affinity towards Cu(II). The BFCs form stable ⁶⁴Cu-radiolabeled complexes and exhibit favorable partition coefficient (log D) values of 0.75-0.95. Among the five compounds tested, the <b>⁶⁴Cu-YW-1</b> and <b>⁶⁴Cu-YW-13</b> complexes exhibit significant staining of amyloid plaques in <i>ex vivo</i> autoradiography studies.

Azide-mediated unusual in situ transformation of Mannich base to Schiff-Mannich base and isolation of their Cu(II) complexes: crystal structure, theoretical inspection and anticancer activities

A new “end-off” compartmental Mannich ligand (HL1) namely 3-((bis(2-methoxyethyl)amino)methyl)-5-bromo-2-hydroxybenzaldehyde containing two methoxyethyl pendant arms and one-CHO functionality has been synthesized through conventional C-C and C-N coupling reactions. On treatment with...

Amino acid-derived bisphenolate palladium complexes as C-C coupling catalysts

A series of amine bisphenol (ABP) pro-ligands featuring amino acid ester pendant arms were prepared. Optimisation of the synthetic method allowed the facile incorporation of naturally occurring, chiral amino acids...

Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Ki-netic, Relaxometric, DFT and SOD Activity Studies.

We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms either at positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclen-oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability (logKMnL = 17.09(2) than the 3,6-PC2A analogue (logKMnL = 15.53(1), 0.15 M NaCl). Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1H relaxivities (r1p = 2.72 and 2.91 mM-1 s -1 for the complexes with 3,6- and 3,9-PC2A, respectively, 25 ºC, 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex 298) are 140106 and 126106 s -1 for [Mn(3,6-PC2A)] and [Mn(3,9- PC2A)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with halflives of 63 and 21 h, respectively, at pH 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)]2- and [Mn(PhDTA)]2- , indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/NBT assay at pH 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable to assist the decomposition of superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by one order of magnitude than that of 3,6-PC2A.

Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Ki-netic, Relaxometric, DFT and SOD Activity Studies.

We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms either at positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclen-oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability (logKMnL = 17.09(2) than the 3,6-PC2A analogue (logKMnL = 15.53(1), 0.15 M NaCl). Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1H relaxivities (r1p = 2.72 and 2.91 mM-1 s -1 for the complexes with 3,6- and 3,9-PC2A, respectively, 25 ºC, 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex 298) are 140106 and 126106 s -1 for [Mn(3,6-PC2A)] and [Mn(3,9- PC2A)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with halflives of 63 and 21 h, respectively, at pH 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)]2- and [Mn(PhDTA)]2- , indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/NBT assay at pH 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable to assist the decomposition of superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by one order of magnitude than that of 3,6-PC2A.