^55/52Mn²⁺ Complexes with a Bispidine-Phosphonate Ligand: High Kinetic Inertness for Imaging Applications

Abstract

Bispidine (3,nonane) provides a rigid and preorganized scaffold that is particularly interesting for the stable and inert complexation of metal ions, especially for their application in medical imaging. In this study, we present the synthesis of two bispidine ligands with N-methanephosphonate (H 4 L 1 ) and N-methanecarboxylate (H 3 L 2 ) substituents as well as the physico-chemical properties of the corresponding Mn 2+ and Zn 2+ complexes. The two complexes [Mn(L 1 )] 2− and [Mn(L 2 )] − have relatively moderate thermodynamic stability constants according to potentiometric titration data. However, they both display an exceptional kinetic inertness, as assessed by transmetallation experiments in the presence of 50 equiv excess of Zn 2+ , showing only ∼40 and 20% of dissociation for [Mn(L 1 )] 2− and [Mn(L 2 )] − , respectively, after 150 days at pH 6 and 37 °C. Proton relaxivities amount to r 1 = 4.31 mM −1 s −1 ([Mn(L 1 )] 2− ) and 3.64 mM −1 s −1 ([Mn(L 2 )] − ) at 20 MHz, 25 °C, and are remarkable for Mn 2+ complexes with one inner-sphere water molecule (q = 1); they are comparable to that of the commercial contrast agent [Gd(DOTA)(H 2 O)] − . The presence of one inner-sphere water molecule and an associative water exchange mechanism was confirmed by temperature-dependent transverse 17 O relaxation rate measurements, which yielded k ex 298 = 0.12 × 10 7 and 5.5 × 10 7 s −1 for the water exchange rate of the phosphonate and the carboxylate complex, respectively. In addition, radiolabeling experiments with 52 Mn were also performed with H 2 (L 1 ) 2− showing excellent radiolabeling properties and quantitative complexation at pH 7 in 15 min at room temperature as well as excellent stability of the complex in various biological media over 24 h.

Structural Variations in Carboxylated Bispidine Ligands: Influence of Positional Isomerism and Rigidity on the Conformation, Stability, Inertness and Relaxivity of their Mn2+ Complexes

“…In contrast, for HL 2 and HL 4 , the formation is slow (~30 min and 2 h are needed to complete the reaction, respectively). Slow complex formation has been previously reported for other bispidine ligands, all in chair‐chair conformation, in this pentadentate family [14–15] …”

“…L 2 has been previously studied. [15] The analysis of these pH-potentiometric titration curves (Figure S19) yielded five logK H values for L 1 and L 3 , while four constants were obtained for L 2 and L 4 (Table 1).…”

“…Slow complex formation has been previously reported for other bispidine ligands, all in chair-chair conformation, in this pentadentate family. [14][15] The slow formation of MnL 2 and MnL 4 complexes likely implies the formation of an intermediate in a rapid equilibrium step where the metal ion has not yet fully entered the bicyclic cage and the bicycle amine remains protonated. The second, rate-determining step involves the deprotonation of the nitrogen, with the subsequent entering of the Mn 2 + into the coordination cavity.…”

Synthesis and characterization of a novel [52Mn]Mn-labelled affibody based radiotracer for HER2+ targeting

“…12 As a result of intensive research conducted during the past 8-10 years, several macrocyclic ligand platforms were identified as possible Mn(II) binders. [15][16][17][18][19][20][21] Hexadentate 3,9-PC2A ( pyclen-3,9-diacetate) chelators form stable and inert monoaquated complexes with Mn(II) resulting in imaging probes allowing for angiographic imaging. pH and Zn(II) responsive smart contrast agents (SCAs) were also designed using the given ligand platform.…”

Mn2+Bispidine Complex Combining Exceptional Stability, Inertness, and MRI Efficiency

“…The bispidine L 4 with the same rigid cavity as L 1 –L 3 but a lower denticity (5 vs 7 or 8), as well as analogues of L 4 , provide a significantly lower complex stability (log K approx. 12 vs >20) and no Mn 2+ selectivity ( K MnL / K ZnL = 4 × 10 –4 ).…”