Cross-Bridged Cyclam with Phosphonate and Phosphinate Pendant Arms: Chelators for Copper Radioisotopes with Fast Complexation

Abstract

Cross-bridged cyclam derivatives bearing two phosphonate (H 4 L 1 ), bis(phosphinate) (H 4 L 2 ), or phosphinate (H 2 L 3 ) pendant arms were synthesized and studied with respect to their application as copper radioisotope carriers in nuclear medicine. The ligands show high macrocycle basicity (pK 1 > 14) and high Cu(II) complex stability (log K = 20−24). The complexation and dissociation kinetics of the Cu(II) complexes were studied by ultraviolet−visible spectroscopy. Phosphonate Cu(II)-H 4 L 1 and bis(phosphinate) Cu(II)-H 4 L 2 complexes form very quickly, reaching quantitative formation within 1 s at pH ∼6 and millimolar concentrations. Conversely, the formation of the phosphinate complex Cu(II)-H 2 L 3 is much slower (9 min at pH ∼6) due to the low stability of the out-of-cage reaction intermediate. All studied complexes are highly kinetically inert, showing half-lives of 120, 11, and 111 h for Cu(II)-H 4 L 1 , Cu(II)-H 4 L 2 , and Cu(II)-H 2 L 3 complexes, respectively, in 1 M HClO 4 at 90 °C. The high thermodynamic stability, fast formation, and extreme kinetic inertness of Cu(II) complexes indicate that phosphonate and bis(phosphinate) derivatives are promising ligands for nuclear medicine.

Endeavor toward Redox-Responsive Transition Metal Contrast Agents Based on the Cross-Bridge Cyclam Platform

“…The macrocyclic cyclam platform (cyclam = 1,4,8,11-tetraazacyclotetradecane) has been widely used for stable complexation of transition metal ions with different purposes. − A rigidified version of cyclam that contains an ethyl chain connecting two opposite N atoms of the macrocycle (CB-cyclam) has also found widespread use as a scaffold for transition metal complexation. − In particular, this macrobicyclic platform improves the kinetic inertness of transition metal complexes for radiopharmaceutical applications. For instance, H 2 CB-TE2A and HCB-TE1A (Chart ) and the related ligands form extremely inert complexes with Cu­(II), − which have been used to develop 64 Cu-based probes for positron emission tomography. − Furthermore, the cross-bridge cyclam platform stabilizes unusual oxidation states in some cases, like the Mn­(IV) complex having two terminal hydroxo ligands [Mn­(CB-TE2Me)­(OH) 2 ] 2+ .…”

Electroreductive Decomplexation and Isomerism of Copper(II) Complexes with Cyclam Ligands for Medical Use

“…In addition, we have included also the dicarboxylate derivative in which the macrocycle is cross-bridged (cb-) by ethylene group as this class of ligands attracted recently increasing attention due to the enormous kinetic inertness. [10,15,16] The experiments were performed using various electrochemical methods at pH 2-12, taking into account also time development and temperature changes. The electrochemical results together with UV-vis spectra and the X-ray crystal structures enabled evaluation and interpretation of acquired data.…”

“…To fulfil this task, we have systematically investigated a set of cyclam derivatives bearing the most typical coordinating pendant arms – carboxylates, phosphonates and phenolates (Figure 1) in order to saturate the Cu II coordination sphere. In addition, we have included also the dicarboxylate derivative in which the macrocycle is cross‐bridged (cb‐) by ethylene group as this class of ligands attracted recently increasing attention due to the enormous kinetic inertness [10,15,16] . The experiments were performed using various electrochemical methods at pH 2–12, taking into account also time development and temperature changes.…”

1,4,7‐Triazacyclononane (tacn) with N,N′‐bridging methylene‐bis(phosphinic acid) group and its complexes

“…[16][17][18][19][20] Recently, we have reported very promising results for azamacrocycles bearing methylene-bis(phosphinic acid) pendant arms. [21][22][23][24][25] These ligands show an excellent metal-binding kinetics. The high acidity of the bis(phosphinic acid) group results in an efficient metal ion binding already in acidic solutions and the phosphinate groups have also a good ability to form hydrogen bonds.…”

“…Our research group has worked with azamacrocycles bearing phosphonate/phosphinate pendant arms for a long time and we have shown that these phosphorus acid pendants often enhance complexation rate [16–20] . Recently, we have reported very promising results for azamacrocycles bearing methylene‐bis(phosphinic acid) pendant arms [21–25] . These ligands show an excellent metal‐binding kinetics.…”